[gmx-users] Doubt about density of states from md trajectory

[Varvdekar Bhagyesh Rajendra]

Dear all,

I have found density of states (Dos) of a protein ligand system from gmx dos 
command of gromacs. I would like to know if it employs the same principle 
component analysis as used in g_covar. If not what are the differences. 

Also the Dos obtained from gmx dos has solid and diffusive components, please 
can anyone shed light on what are they exactly?

Thank you,

Bhagyesh

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[gmx-users] Doubt about thermostat in MD

[Varvdekar Bhagyesh Rajendra]

Dear all,

I have to find vibrational spectrum of a protein-ligand complex in water using 
MD. Can anyone please suggest me what thermostats would be suited for NVT 
equilibration, NPT equilibration and MD production. I have read that for NVT, 
berendsen is suited while for NPT and MD part, nose-hoover  is used.


Also, what constraints would be suited for finding vibrational spectrum. I plan 
to use all-H as constraints.



Thank you,

Bhagyesh
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[gmx-users] Doubt about g_dos

[Varvdekar Bhagyesh Rajendra]

Dear all,

I am attempting to find the Vibrational density of states of protein bound to 
ligand in a water box using the command g_dos. To do so, should I extract the 
protein part from the entire trajectory file containing coordinates and 
velocities of all atoms (trr file) and then run g_dos on the resultant partial 
trajectory containing only protein coordinates and velocities ? or the entire 
trajectory which of course doesn't make sense ?


Thank you,

Bhagyesh
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[gmx-users] Doubt about hessian matrix in Normal mode analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I used the following command to print ascii format of the hessian matrix to a 
file from the default mtx format of gromacs obtained after normal mode analysis.

gmxdump_d -mtx nm.mtx > hessian_matrix.dat

I would like to confirm the way the hessian matrix is written in this new ascii 
file. Is the following way correct where the x, y, z coordinates of the first 
atom are considered, then second atom and so on and so forth in each row and 
column and the matrix elements are the second order derivatives of potential 
energy with respect to its corresponding row and column coordinates ?

Here x_i = x coordinate of the i_th atom, y_i = y coordinate of the i_th atom, 
z_i = z coordinate of the i_th atom.
And the matrix elements M are the second order of U (Potential energy) with 
respect to its corresponding row and column coordinate i.e. M = d^2 U / dx_i d_i

   | x1 | y1 | z1 | x2 | y2 | z2 | ... | x_n | y_n | z_n |
-|
x1 | M  |  M | M  |  M | M  | M  | ...
---
y1 | M  |  M | M  |  M | M  | M  | ...
--
z1 | M  |  M | M  |  M | M  | M  | ...
--
x2 | M  |  M | M  |  M | M  | M  | ...
---
y2 | M  |  M | M  |  M | M  | M  | ...
--
z2 | M  |  M | M  |  M | M  | M  | ...
--
.
.
.
x_N
y_N
z_N 
--


I got some hint from the following past thread but I would like to confirm the 
same.

https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2015-June/098468.html

Thank you,

Bhagyesh
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[gmx-users] Doubt about hessian matrix in Normal mode analysis

[Varvdekar Bhagyesh Rajendra]

Dear all,

I used the following command to print ascii format of the hessian matrix to a 
file from the default mtx format of gromacs obtained after normal mode analysis.

gmxdump_d -mtx nm.mtx > hessian_matrix.dat

I would like to confirm the way the hessian matrix is written in this new ascii 
file. Is the following way correct where the x, y, z coordinates of the first 
atom are considered, then second atom and so on and so forth in each row and 
column and the matrix elements are the second order derivatives of potential 
energy with respect to its corresponding row and column coordinates ?

Here x_i = x coordinate of the i_th atom, y_i = y coordinate of the i_th atom, 
z_i = z coordinate of the i_th atom.
And the matrix elements M are the second order of U (Potential energy) with 
respect to its corresponding row and column coordinate i.e. M = d^2 U / dx_i d_i

   | x1 | y1 | z1 | x2 | y2 | z2 | ... | x_n | y_n | z_n |
-|
x1 | M  |  M | M  |  M | M  | M  | ...
---
y1 | M  |  M | M  |  M | M  | M  | ...
--
z1 | M  |  M | M  |  M | M  | M  | ...
--
x2 | M  |  M | M  |  M | M  | M  | ...
---
y2 | M  |  M | M  |  M | M  | M  | ...
--
z2 | M  |  M | M  |  M | M  | M  | ...
--
.
.
.
x_N
y_N
z_N 
--


I got some hint from the following past thread but I would like to confirm the 
same.

https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2015-June/098468.html

Thank you,

Bhagyesh
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Re: [gmx-users] gromacs rerun calculate the energy

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

To get an estimate of the long range interactions in LIE calculations for 
protein-ligand binding energy calculations, is it reasonable to change the 
coulomb type to reaction-field zero instead of changing the rcoulomb from 1.0 
nanometre to half of the water box, and the coulombtype from PME to cut-off ? 
If yes, what should be the rcoulomb with coulombtype = reaction-field zero ?

Also, instead of changing rcoulomb from 1.0 nanometre to half of the water box, 
does changing it to lets say the box length have better accuracy?

Thank you,

Bhagyesh

- Original Message -
From: "Justin Lemkul" 
To: gmx-us...@gromacs.org
Sent: Tuesday, August 1, 2017 4:20:54 AM
Subject: Re: [gmx-users] gromacs rerun calculate the energy

On 7/31/17 8:03 AM, 王珍 wrote:
> Hi all,
>I used Gromacs run the biological system,  which contains water, 
> ions(Na+,Cl-), and nucleic. I used gromacs run the system, and the 
> coulombtype was PME and the cutoff was 10 angstrom,  then I want to use the 
> commond rerun to calculate the interaction of resid 1 and resid 2, I add the 
> energygrps in my mdp, and the coulombtype was PME, the .edr file can be 
> obtained. Then I use g_energy to calculate the coulomb interaction. I have 
> three question.
> first, when the rcoulomb=10 angstrom, and coulombtype=PME, within 10 
> angstrom, is PME algorithm using ?
> 

Yes, because there are both real-space (within rcoulomb) and Fourier space 
(long-range) terms.

> 
> 
> second, The PME algorithm dived into long range interaction and short range 
> interaction, whereas we only calculate the short range of the coulomb energy 
> using Gromacs, can we obtain the long range of the coulomb energy?
> 

Perhaps by clever use of convert-tpr to zero out charges of certain groups 
(there is a post in the archive from some time ago about this) but I am 
skeptical about the value of such a number.

> 
> 
> Third, when I use rerun to calculate the coulomb energy, the rcoulomb from 
> 1.0 nanometre change to half of the water box I built, and the coulombtype 
> from PME to cut-off, is it reasonable to calculate the coulomb energy?
> 

This is probably the more straightforward way to determine a reasonable 
estimate 
of the longer-range energy contributions.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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[gmx-users] Doubt about hessian matrix in Normal mode analysis

[Varvdekar Bhagyesh Rajendra]

Dear all,

I used the following command to print ascii format of the hessian matrix to a 
file from the default mtx format of gromacs obtained after normal mode analysis.

gmxdump_d -mtx nm.mtx > hessian_matrix.dat

I would like to confirm the way the hessian matrix is written in this new ascii 
file. Is the following way correct where the x, y, z coordinates of the first 
atom are considered, then second atom and so on and so forth in each row and 
column and the matrix elements are the second order derivatives of potential 
energy with respect to its corresponding row and column coordinates ?

Here x_i = x coordinate of the i_th atom, y_i = y coordinate of the i_th atom, 
z_i = z coordinate of the i_th atom.
And the matrix elements M are the second order of U (Potential energy) with 
respect to its corresponding row and column coordinate i.e. M = d^2 U / dx_i d_i

   | x1 | y1 | z1 | x2 | y2 | z2 | ... | x_n | y_n | z_n |
-|
x1 | M  |  M | M  |  M | M  | M  | ...
---
y1 | M  |  M | M  |  M | M  | M  | ...
--
z1 | M  |  M | M  |  M | M  | M  | ...
--
x2 | M  |  M | M  |  M | M  | M  | ...
---
y2 | M  |  M | M  |  M | M  | M  | ...
--
z2 | M  |  M | M  |  M | M  | M  | ...
--
.
.
.
x_N
y_N
z_N 
--


Thank you,

Bhagyesh
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[gmx-users] Doubt about hessian matrix in Normal mode analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I used the following command to print ascii format of the hessian matrix to a 
file from the default mtx format of gromacs obtained after normal mode analysis.

gmxdump_d -mtx nm.mtx > hessian_matrix.dat

I would like to confirm the way the hessian matrix is written in this new ascii 
file. Is the following way correct where the x, y, z coordinates of the first 
atom are considered, then second atom and so on and so forth in each row and 
column and the matrix elements are the second order derivatives of potential 
energy with respect to its corresponding row and column coordinates ?

Here x_i = x coordinate of the i_th atom, y_i = y coordinate of the i_th atom, 
z_i = z coordinate of the i_th atom.
And the matrix elements M are the second order of U (Potential energy) with 
respect to its corresponding row and column coordinate i.e. M = d^2 U / dx_i d_i

   | x1 | y1 | z1 | x2 | y2 | z2 | ... | x_n | y_n | z_n |
-|
x1 | M  |  M | M  |  M | M  | M  | ...
---
y1 | M  |  M | M  |  M | M  | M  | ...
--
z1 | M  |  M | M  |  M | M  | M  | ...
--
x2 | M  |  M | M  |  M | M  | M  | ...
---
y2 | M  |  M | M  |  M | M  | M  | ...
--
z2 | M  |  M | M  |  M | M  | M  | ...
--
.
.
.
x_N
y_N
z_N 
--


Thank you,

Bhagyesh
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[gmx-users] Doubt about edr file after normal mode analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I attempted to write the energy file (edr file) after performing normal mode 
analysis (using integrator = nm), but couldn't find gromacs writing nm.edr file 
at the end of the nm analysis similar to the way it writes em.edr after energy 
minimization. So firstly, is it plausible to write the edr file after nm 
analysis and if it is, what correction should I implement in the following set 
of gromacs commands I executed, to pull it off?

grompp_d -f nmnopbc.mdp -c em.gro -p topol.top -o nm.tpr

mdrun_d -v -deffnm nm -e nm.edr



Thank you,
Bhagyesh
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Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

It would be helpful if you please explain in a bit more detail about the impact 
of the settings of table-extension. The manual says "Extension of the 
non-bonded potential lookup tables beyond the largest cut-off distance", but a 
better insight from you would be definitely more very useful.

I have a slightest idea that it is useful to save computational time. It that 
is considered true, it shouldn't affect the results, should it?

I would appreciate if you could explain how increasing table-extension can 
cause permit distorted structures. 

I performed a short study of the effect on increasing table-extension from 1 nm 
to 10 nm onwards in increments of 1 nm. The inter and intra molecular energies  
increased from 1 nm to 4 nm and then were almost the same and with the 
minimization without any free energy code. Hence, I suspect that 
table-extension with 4 nm onwards takes into account all interactions while the 
free energy change goes on. I would appreciate if you could offer any comment 
on my deduction. 

I couldn't find any distorted structures while the study though, could you 
suggest any criteria so as to consider if any structure has evolved into a 
distorted one?

Is there any other way where I can avoid the said warning other than increasing 
table-extension and maintaining couple-intramol = no in my minimizing code with 
the free energy addendum.

Thank you,

Bhagyesh

- Original Message -----
From: "Varvdekar Bhagyesh Rajendra" <bhagyesh.varvde...@research.iiit.ac.in>
To: gmx-us...@gromacs.org
Sent: Friday, June 30, 2017 2:24:09 AM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

Dear Justin,

It would be helpful if you please explain in a bit more detail about the impact 
of the settings of table-extension. The manual says "Extension of the 
non-bonded potential lookup tables beyond the largest cut-off distance", but a 
better insight from you would be definitely more very useful.

I have a slightest idea that it is useful to save computational time. It that 
is considered true, it shouldn't affect the results, should it?

I would appreciate if you could explain how increasing table-extension can 
cause permit distorted structures. 

Is there any other way where I can avoid the said warning other than increasing 
table-extension and maintaining couple-intramol = no in my minimizing code with 
the free energy addendum.

Thank you,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Thursday, June 29, 2017 6:48:25 PM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/29/17 5:11 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I am getting the same following warning even after minimizing the system 
> twice using cg integrator. This is only when the free energy stuff is 
> inserted in the energy minimization code.
> 
> " WARNING: Listed nonbonded interaction between particles 2263 and 2298 at 
> distance 3f which is larger than the table limit 3f nm.
> 
> This is likely either a 1,4 interaction, or a listed interaction inside a 
> smaller molecule you are decoupling during a free energy calculation. Since 
> interactions at distances beyond the table cannot be computed, they are 
> skipped until they are inside the table limit again. You will only see this 
> message once, even if it occurs for several interactions.
> 
> IMPORTANT: This should not happen in a stable simulation, so there is 
> probably something wrong with your system. Only change the table-extension 
> distance in the mdp file if you are really sure that is the reason. "
> 
> 
> When the system is minimized without free energy code, it shows no warning. 
> Hence, I suppose it is due to the free energy code itself with 
> couple-intramol = no.
> 
> I found the warning disappears when couple-intramol = yes. But this is not I 
> would like to do, since intra molecular interactions need not be 
> scaled/perturbed.
> 
> It's definitely true that the "listed interaction inside a smaller molecule 
> you are decoupling during a free energy calculation".
> 
> When the table-extension is increased to 4 nm with couple-intramol = no, the 
> warning again disappears. Should I go forward with this setting and how will 
> it affect the energy minimization of my system?
> 

Increasing the table-extension means mdrun will permit distorted structures 
that 
may be totally unreasonable.  It is generally unwise to increase it, and 
especially if you're increasing it that much.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Fac

Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

It would be helpful if you please explain in a bit more detail about the impact 
of the settings of table-extension. The manual says "Extension of the 
non-bonded potential lookup tables beyond the largest cut-off distance", but a 
better insight from you would be definitely more very useful.

I have a slightest idea that it is useful to save computational time. It that 
is considered true, it shouldn't affect the results, should it?

I would appreciate if you could explain how increasing table-extension can 
cause permit distorted structures. 

Is there any other way where I can avoid the said warning other than increasing 
table-extension and maintaining couple-intramol = no in my minimizing code with 
the free energy addendum.

Thank you,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Thursday, June 29, 2017 6:48:25 PM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/29/17 5:11 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I am getting the same following warning even after minimizing the system 
> twice using cg integrator. This is only when the free energy stuff is 
> inserted in the energy minimization code.
> 
> " WARNING: Listed nonbonded interaction between particles 2263 and 2298 at 
> distance 3f which is larger than the table limit 3f nm.
> 
> This is likely either a 1,4 interaction, or a listed interaction inside a 
> smaller molecule you are decoupling during a free energy calculation. Since 
> interactions at distances beyond the table cannot be computed, they are 
> skipped until they are inside the table limit again. You will only see this 
> message once, even if it occurs for several interactions.
> 
> IMPORTANT: This should not happen in a stable simulation, so there is 
> probably something wrong with your system. Only change the table-extension 
> distance in the mdp file if you are really sure that is the reason. "
> 
> 
> When the system is minimized without free energy code, it shows no warning. 
> Hence, I suppose it is due to the free energy code itself with 
> couple-intramol = no.
> 
> I found the warning disappears when couple-intramol = yes. But this is not I 
> would like to do, since intra molecular interactions need not be 
> scaled/perturbed.
> 
> It's definitely true that the "listed interaction inside a smaller molecule 
> you are decoupling during a free energy calculation".
> 
> When the table-extension is increased to 4 nm with couple-intramol = no, the 
> warning again disappears. Should I go forward with this setting and how will 
> it affect the energy minimization of my system?
> 

Increasing the table-extension means mdrun will permit distorted structures 
that 
may be totally unreasonable.  It is generally unwise to increase it, and 
especially if you're increasing it that much.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
-- 
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Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I am getting the same following warning even after minimizing the system twice 
using cg integrator. This is only when the free energy stuff is inserted in the 
energy minimization code.

" WARNING: Listed nonbonded interaction between particles 2263 and 2298 at 
distance 3f which is larger than the table limit 3f nm.

This is likely either a 1,4 interaction, or a listed interaction inside a 
smaller molecule you are decoupling during a free energy calculation. Since 
interactions at distances beyond the table cannot be computed, they are skipped 
until they are inside the table limit again. You will only see this message 
once, even if it occurs for several interactions.

IMPORTANT: This should not happen in a stable simulation, so there is probably 
something wrong with your system. Only change the table-extension distance in 
the mdp file if you are really sure that is the reason. "


When the system is minimized without free energy code, it shows no warning. 
Hence, I suppose it is due to the free energy code itself with couple-intramol 
= no.

I found the warning disappears when couple-intramol = yes. But this is not I 
would like to do, since intra molecular interactions need not be 
scaled/perturbed.

It's definitely true that the "listed interaction inside a smaller molecule you 
are decoupling during a free energy calculation". 

When the table-extension is increased to 4 nm with couple-intramol = no, the 
warning again disappears. Should I go forward with this setting and how will it 
affect the energy minimization of my system?

Best Regards,
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, June 28, 2017 7:17:34 AM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/27/17 7:43 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> When the system is minimized with full interactions with no free energy code, 
> I see no warnings and the systems is minimized properly.
> 
> However, when the free energy code is added with couple-intramol = no, I 
> encounter the said warning, but still the system can be minimized ignoring 
> the warning.
> 
> When the free energy code is added with couple-intramol = yes, there's no 
> warning, but the system is again well minimized.
> 

You may need several rounds of energy minimization to get a stable result.  
Your 
final minimization and equilibration should be done under the 
conditions/settings that make the most sense for you to model.

-Justin

> I would like to learn if its reasonable to ignore the warning in the case 
> where couple-intramol = no, since I am dealing with a peptide and 
> intramolecular interactions can suppress the intermolecular interactions.
> 
> I intend to perform normal-mode calculations on the resulting intermediates 
> which are divergent from the Binding energy simulations requiring 
> convergence. Hence, I presume there shouldn't be much complication in this 
> case. I understand the approach seems quite outlandish, but still I aspire to 
> execute the same. Any opinions and/or suggestions in this procedure will be 
> greatly helpful.
> 
> Many thanks,
> 
> Bhagyesh.
> 
> 
> - Original Message -
> From: "Justin Lemkul" <jalem...@vt.edu>
> To: gmx-us...@gromacs.org
> Sent: Tuesday, June 27, 2017 6:42:33 PM
> Subject: Re: [gmx-users] Doubt about Free Energy control Minimization
> 
> On 6/26/17 9:09 AM, Varvdekar Bhagyesh Rajendra wrote:
>> Dear Justin,
>>
>> I have encountered the following warning when I used the following code to 
>> minimize my protein-ligand system when the interaction potential energy 
>> between the protein and the ligand are multiplied by 0.9, 0.8, 0.7,..., 0.2, 
>> 0.1.
>>
>> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
>>
>> Warning: 1-4 interaction between 2263 and 2298 at distance 1.004 which is 
>> larger than the 1-4 table size 1.000 nm
>> These are ignored for the rest of the simulation
>> This usually means your system is exploding,
>> if not, you should increase table-extension in your mdp file
>> or with user tables increase the table size
>>
>>
>> I suppose this error is due to setting couple-intramol = no. When it is set 
>> to yes, the warning vanishes.
>>
>> But, this is my desired setting since, I do not intend to scale the intra 
>> molecular interactions even though the ligand is a peptide. Is it reasonable 
>> to ignore the warning. If not , how can it affect my resulting structure ? 
>> And are all such interaction "ignored for the rest of the simulation" ?
>>
> 
> 

Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

When the system is minimized with full interactions with no free energy code, I 
see no warnings and the systems is minimized properly. 

However, when the free energy code is added with couple-intramol = no, I 
encounter the said warning, but still the system can be minimized ignoring the 
warning.

When the free energy code is added with couple-intramol = yes, there's no 
warning, but the system is again well minimized.

I would like to learn if its reasonable to ignore the warning in the case where 
couple-intramol = no, since I am dealing with a peptide and intramolecular 
interactions can suppress the intermolecular interactions.

I intend to perform normal-mode calculations on the resulting intermediates 
which are divergent from the Binding energy simulations requiring convergence. 
Hence, I presume there shouldn't be much complication in this case. I 
understand the approach seems quite outlandish, but still I aspire to execute 
the same. Any opinions and/or suggestions in this procedure will be greatly 
helpful.

Many thanks,

Bhagyesh.


- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Tuesday, June 27, 2017 6:42:33 PM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/26/17 9:09 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I have encountered the following warning when I used the following code to 
> minimize my protein-ligand system when the interaction potential energy 
> between the protein and the ligand are multiplied by 0.9, 0.8, 0.7,..., 0.2, 
> 0.1.
> 
> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
> 
> Warning: 1-4 interaction between 2263 and 2298 at distance 1.004 which is 
> larger than the 1-4 table size 1.000 nm
> These are ignored for the rest of the simulation
> This usually means your system is exploding,
> if not, you should increase table-extension in your mdp file
> or with user tables increase the table size
> 
> 
> I suppose this error is due to setting couple-intramol = no. When it is set 
> to yes, the warning vanishes.
> 
> But, this is my desired setting since, I do not intend to scale the intra 
> molecular interactions even though the ligand is a peptide. Is it reasonable 
> to ignore the warning. If not , how can it affect my resulting structure ? 
> And are all such interaction "ignored for the rest of the simulation" ?
> 

So the system is unstable.  Try minimizing with full interactions before doing 
anything funny with scaling.  And I repeat my caution to you that trying to do 
an alchemical transformation of a peptide is a very unwise choice.  You'll 
never 
get the simulations to converge in a practical amount of time.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I have encountered the following warning when I used the following code to 
minimize my protein-ligand system when the interaction potential energy between 
the protein and the ligand are multiplied by 0.9, 0.8, 0.7,..., 0.2, 0.1.

http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp

Warning: 1-4 interaction between 2263 and 2298 at distance 1.004 which is 
larger than the 1-4 table size 1.000 nm
These are ignored for the rest of the simulation
This usually means your system is exploding,
if not, you should increase table-extension in your mdp file
or with user tables increase the table size


I suppose this error is due to setting couple-intramol = no. When it is set to 
yes, the warning vanishes.

But, this is my desired setting since, I do not intend to scale the intra 
molecular interactions even though the ligand is a peptide. Is it reasonable to 
ignore the warning. If not , how can it affect my resulting structure ? And are 
all such interaction "ignored for the rest of the simulation" ?

Apologies for the previous incomplete mail.

Best Regards,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, June 14, 2017 4:50:58 AM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/13/17 4:31 PM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I aspire to derive energy-minimum structures when the interaction potential 
> energy between the protein and the ligand are multiplied by 0.9, 0.8, 
> 0.7,..., 0.2, 0.1.
> 
> I presume the following Free Energy minimization code mentioned in gromacs 
> tutorial may do the trick. I would appreciate if you could please verify if 
> it produces my intended result.
> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
> 

Possibly, but the outcomes may be unphysical.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I have encountered the following error when I used the 

http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
> 
Error:

Warning: 1-4 interaction between 2263 and 2298 at distance 1.004 which is 
larger than the 1-4 table size 1.000 nm
These are ignored for the rest of the simulation
This usually means your system is exploding,
if not, you should increase table-extension in your mdp file
or with user tables increase the table size


Best Regards,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, June 14, 2017 4:50:58 AM
Subject: Re: [gmx-users] Doubt about Free Energy control Minimization

On 6/13/17 4:31 PM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I aspire to derive energy-minimum structures when the interaction potential 
> energy between the protein and the ligand are multiplied by 0.9, 0.8, 
> 0.7,..., 0.2, 0.1.
> 
> I presume the following Free Energy minimization code mentioned in gromacs 
> tutorial may do the trick. I would appreciate if you could please verify if 
> it produces my intended result.
> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp
> 

Possibly, but the outcomes may be unphysical.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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[gmx-users] Doubt about Free Energy control Minimization

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I aspire to derive energy-minimum structures when the interaction potential 
energy between the protein and the ligand are multiplied by 0.9, 0.8, 0.7,..., 
0.2, 0.1.

I presume the following Free Energy minimization code mentioned in gromacs 
tutorial may do the trick. I would appreciate if you could please verify if it 
produces my intended result.
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/Files/em_steep.mdp

Thanking in anticipation,

Best Regards,

Bhagyesh
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[gmx-users] Doubt about g_lie

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I have used PME in the production runs of my systems for finding Delta 
G_Binding using g_lie. But many threads on Gromacs forum warn against it and 
advise to rerun the whole trajectory using Reaction field Zero, but the cutoff 
for this rerun is not clearly given. Some threads say a cutoff with large 
cutoff using RF-0 is necessary. Can you please uggest as to what 
cutoff(Relative to the system) should be given while re-running the trajectory 
and what all changes have to be done in the original mdp file(which uses PME). 
Also, a brief explanation for the whole process for the need of the re-run 
would be beneficial. Following are the changes I made after studying the past 
threads:

;; With PME  ;;; | ;; Re-Run without PME ;;
-
 ; Neighborsearching |  ; Neighborsearching
  ns_type = grid  ; search neighboring grid  |  ns_type = grid  
; search neighboring grid cells
  nstlist = 5 ; 10 fs|  nstlist = 5 
; 10 fs
  rlist   = 0.9   ; short-range neighborlist |  rlist   = 1.2   
; short-range neighborlist cutoff (nm)  
  
  rcoulomb= 0.9   ; short-range electrostatic|  rcoulomb= 0.9   
; short-range electrostatic cutoff (in nm)
  rvdw= 1.4   ; short-range van der Waals|  rvdw= 1.4   
; short-range van der Waals cutoff (in nm)
 |
; Electrostatics | ; Electrostatics
coulombtype = PME| coulombtype  =  
Reaction-Field-zero 
 | epsilon_rf  =  0
---

Best Regards,

Bhagyesh
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Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

So if I am interpreting it correct, it is reasonable if sc-coul = no even when 
partial coulomb interpolation takes place during transition from couple-lambda0 
= none to couple-lambda1 = vdw-q , right?

Thank you for the reply,

-
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Tuesday, June 13, 2017 2:18:30 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

On 6/12/17 11:47 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I have compiled the following free energy code for use in the g_bar program 
> for finding Binding affinity of a Protein-ligand complex, with ligand being a 
> peptide. I would appreciate if you could please verify it's correctness and 
> perhaps suggest any valuable improvements, if deemed necessary.
> 
> I am not sure about the input in the parameters for: *sc-coul* and 
> *couple-intramol* though.
> 
> Since couple-lambda0 = none and couple-lambda1 = vdw-q, I assume coulomb 
> interpolation must be taking place, and sc-coul should be *yes*.
> 

Not necessarily.  Scaling Coulombic interactions linearly is what is more 
commonly done.

> Also, as my ligand is a peptide, I presume couple-intramol should also be 
> *yes*.
> 

If you're dealing with a peptide, you shouldn't be doing an alchemical 
transformation.  It will probably never converge.  PMF or MM/PBSA are much 
better approaches for determining binding free energies for these types of 
systems.

-Justin

> 
> ; Free energy control
> 
> free_energy  = yes
> init_lambda_state= 0
> delta_lambda = 0
> calc_lambda_neighbors= 1; only immediate neighboring windows
> ; Vectors of lambda specified here
> ; Each combination is an index that is retrieved from init_lambda_state for 
> each simulation
> 
> ; init_lambda_state0123456789
> 10   11   12   13   14   15   16   17   18   19   20   21   22   23   24   25 
>   26   27   28   29   30   31   32   33   34   35   36   37   38   39   40
> vdw_lambdas  = 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 
> 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 1.00 1.00 1.00 1.00 
> 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 
> 1.00
> coul_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.10 0.15 0.20 
> 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 
> 1.00
> ; We are not transforming any bonded or restrained interactions
> bonded_lambdas   = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00
> restraint_lambdas= 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00
> mass_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00
> temperature_lambdas  = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
> 0.00
> 
> ; Options for the decoupling
> sc-alpha = 0.5
> sc-coul  = ??   ; As linear interpolation of Coulomb 
> takes place, I suppose it should be *yes*
> sc-power = 1.0
> sc-sigma = 0.3
> couple-moltype   = Protein_chain_B  ; name of moleculetype to 
> decouple
> couple-lambda0   = none ; interactions are turned off in the 
> beginning
> couple-lambda1   = vdw-q; all interactions are on in the end
> couple-intramol  = ??   ; since my ligand is a peptide, I suppose 
> the intramol interactions should be *yes*
> nstdhdl  = 10
> 
> 
> Thanking in anticipation,
> 
> Best Regards,
> 
> Bhagyesh
> 
> 
> ----- Original Message -
> From: "Justin Lemkul" <jalem...@vt.edu>
> To: gmx-us...@gromacs.org
> Sent: Sunday, June 11, 2017 7:01:26 AM
> Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar
> 
> On 6/10/17 6:15 AM, Varvdekar Bhagyesh Rajendra wrote:
>> Dear Justin,
>>
>> Just so we are on the same page, 

Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I have compiled the following free energy code for use in the g_bar program for 
finding Binding affinity of a Protein-ligand complex, with ligand being a 
peptide. I would appreciate if you could please verify it's correctness and 
perhaps suggest any valuable improvements, if deemed necessary.

I am not sure about the input in the parameters for: *sc-coul* and 
*couple-intramol* though. 

Since couple-lambda0 = none and couple-lambda1 = vdw-q, I assume coulomb 
interpolation must be taking place, and sc-coul should be *yes*.

Also, as my ligand is a peptide, I presume couple-intramol should also be *yes*.


; Free energy control

free_energy  = yes
init_lambda_state= 0
delta_lambda = 0
calc_lambda_neighbors= 1; only immediate neighboring windows
; Vectors of lambda specified here
; Each combination is an index that is retrieved from init_lambda_state for 
each simulation

; init_lambda_state012345678910 
  11   12   13   14   15   16   17   18   19   20   21   22   23   24   25   26 
  27   28   29   30   31   32   33   34   35   36   37   38   39   40
vdw_lambdas  = 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 
0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 1.00 1.00 1.00 1.00 1.00 
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
coul_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.10 0.15 0.20 0.25 
0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00
; We are not transforming any bonded or restrained interactions 
bonded_lambdas   = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
restraint_lambdas= 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
mass_lambdas = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
temperature_lambdas  = 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 
0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

; Options for the decoupling
sc-alpha = 0.5
sc-coul  = ??   ; As linear interpolation of Coulomb takes 
place, I suppose it should be *yes*
sc-power = 1.0
sc-sigma = 0.3 
couple-moltype   = Protein_chain_B  ; name of moleculetype to 
decouple
couple-lambda0   = none ; interactions are turned off in the 
beginning
couple-lambda1   = vdw-q; all interactions are on in the end
couple-intramol  = ??   ; since my ligand is a peptide, I suppose 
the intramol interactions should be *yes*
nstdhdl  = 10


Thanking in anticipation,

Best Regards,

Bhagyesh


- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Sunday, June 11, 2017 7:01:26 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

On 6/10/17 6:15 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> Just so we are on the same page, this means that if I don't touch the 
> topology file and use the following mdp snippet, charges *are present* in the 
> topology file for the ligand group and they are automatically set to zero 
> while turning on vdW interactions (from 0 to 1) right ? Hence, there is no 
> need to manually set charges to zero (The old style of doing the 
> calculations), right?.
> 

Yes.  You can easily confirm this using energygrps between your transformed 
molecule and the rest of the system.  Coul-SR should be zero.

> Then the charges too, are turned off from 0 to 1? (1 state being the actual 
> charges present in the topology file).
> 

Charges are turned *on* if they are defined as off in the A-state (lambda=0) 
and 
on in the B-state (lambda=1).

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Mark,

I humbly disagree that the observations could not provide an insight into the 
physical systems because a previous the work provides a reasonable proof: 
"Theory and normal-mode analysis of change in protein vibrational dynamics on 
ligand binding", DOI: 10.1021/jp909677p

I wish to extend the said work and it speaks about the generation of a 
hypothetical “intermediate” state, without the ligand force field but with a 
structure resembling to that of the Bound complex state. It reveals that during 
the binding occurs from intermediate to the bound state, the vibrational 
entropies of both the protein and the ligand decrease, thereby predicting the 
physical state properties.

Even if the hypothesis is not true, I wish to proceed the required procedure 
and it would be helpful if you could provide any valuable revelation of doing 
the same in gromacs.

Best Regards,

Bhagyesh

- Original Message -
From: "Mark Abraham" <mark.j.abra...@gmail.com>
To: gmx-us...@gromacs.org
Sent: Monday, June 12, 2017 2:43:53 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

Hi,

On Sun, Jun 11, 2017 at 10:39 PM Varvdekar Bhagyesh Rajendra <
bhagyesh.varvde...@research.iiit.ac.in> wrote:

> Dear Mark,
>
> Unless I'm mistaken, even though they are non-physical states and do not
> exist in reality, they have the required modification in the actual
> physical state (precisely, the non bonded interaction between protein and
> ligand) that I actually need and I wish to use the same and do Normal mode
> calculations to study the effect of the said perturbation at each lambda
> from 0 to 1.
>
> I would appreciate any suggestions to undertake the above quest.
>

I expect that the numbers you seek will be computed. But you're also going
to scale down e.g. the ligand-solute interactions, and IMO it's unlikely
you'll observe anything that you can claim is insight into the physical
systems.

Mark


> Best Regards,
>
> Bhagyesh
>
> - Original Message -
> From: "Mark Abraham" <mark.j.abra...@gmail.com>
> To: gmx-us...@gromacs.org
> Sent: Sunday, June 11, 2017 9:22:51 PM
> Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar
>
> Hi,
>
> To what end? These are non-physical states.
>
> Mark
>
> On Sun, 11 Jun 2017 16:28 Varvdekar Bhagyesh Rajendra <
> bhagyesh.varvde...@research.iiit.ac.in> wrote:
>
> > Dear Justin,
> >
> > Thank you for the valuable insight.
> >
> > While on the same subject, can you give any comments on the possibility
> of
> > using the same Free energy code in Gromacs to scale the non bonded
> > interactions between protein & ligand while simultaneously doing Normal
> > Mode analysis on the scaled interaction conformation to study the effect
> of
> > the scaled interactions.
> >
> > If its not plausible in Gromacs, can you suggest any other software.
> >
> > Best Regards,
> >
> > Bhagyesh
> >
> > - Original Message -
> > From: "Justin Lemkul" <jalem...@vt.edu>
> > To: gmx-us...@gromacs.org
> > Sent: Sunday, June 11, 2017 7:01:26 AM
> > Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar
> >
> > On 6/10/17 6:15 AM, Varvdekar Bhagyesh Rajendra wrote:
> > > Dear Justin,
> > >
> > > Just so we are on the same page, this means that if I don't touch the
> > topology file and use the following mdp snippet, charges *are present* in
> > the topology file for the ligand group and they are automatically set to
> > zero while turning on vdW interactions (from 0 to 1) right ? Hence, there
> > is no need to manually set charges to zero (The old style of doing the
> > calculations), right?.
> > >
> >
> > Yes.  You can easily confirm this using energygrps between your
> transformed
> > molecule and the rest of the system.  Coul-SR should be zero.
> >
> > > Then the charges too, are turned off from 0 to 1? (1 state being the
> > actual charges present in the topology file).
> > >
> >
> > Charges are turned *on* if they are defined as off in the A-state
> > (lambda=0) and
> > on in the B-state (lambda=1).
> >
> > -Justin
> >
> > --
> > ==
> >
> > Justin A. Lemkul, Ph.D.
> > Ruth L. Kirschstein NRSA Postdoctoral Fellow
> >
> > Department of Pharmaceutical Sciences
> > School of Pharmacy
> > Health Sciences Facility II, Room 629
> > University of Maryland, Baltimore
> > 20 Penn St.
> > Baltimore, MD 21201
> >
> > jalem...@outerbanks.umaryland.edu | 

Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Mark,

Unless I'm mistaken, even though they are non-physical states and do not exist 
in reality, they have the required modification in the actual physical state 
(precisely, the non bonded interaction between protein and ligand) that I 
actually need and I wish to use the same and do Normal mode calculations to 
study the effect of the said perturbation at each lambda from 0 to 1.

I would appreciate any suggestions to undertake the above quest.

Best Regards,

Bhagyesh

- Original Message -
From: "Mark Abraham" <mark.j.abra...@gmail.com>
To: gmx-us...@gromacs.org
Sent: Sunday, June 11, 2017 9:22:51 PM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

Hi,

To what end? These are non-physical states.

Mark

On Sun, 11 Jun 2017 16:28 Varvdekar Bhagyesh Rajendra <
bhagyesh.varvde...@research.iiit.ac.in> wrote:

> Dear Justin,
>
> Thank you for the valuable insight.
>
> While on the same subject, can you give any comments on the possibility of
> using the same Free energy code in Gromacs to scale the non bonded
> interactions between protein & ligand while simultaneously doing Normal
> Mode analysis on the scaled interaction conformation to study the effect of
> the scaled interactions.
>
> If its not plausible in Gromacs, can you suggest any other software.
>
> Best Regards,
>
> Bhagyesh
>
> - Original Message -
> From: "Justin Lemkul" <jalem...@vt.edu>
> To: gmx-us...@gromacs.org
> Sent: Sunday, June 11, 2017 7:01:26 AM
> Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar
>
> On 6/10/17 6:15 AM, Varvdekar Bhagyesh Rajendra wrote:
> > Dear Justin,
> >
> > Just so we are on the same page, this means that if I don't touch the
> topology file and use the following mdp snippet, charges *are present* in
> the topology file for the ligand group and they are automatically set to
> zero while turning on vdW interactions (from 0 to 1) right ? Hence, there
> is no need to manually set charges to zero (The old style of doing the
> calculations), right?.
> >
>
> Yes.  You can easily confirm this using energygrps between your transformed
> molecule and the rest of the system.  Coul-SR should be zero.
>
> > Then the charges too, are turned off from 0 to 1? (1 state being the
> actual charges present in the topology file).
> >
>
> Charges are turned *on* if they are defined as off in the A-state
> (lambda=0) and
> on in the B-state (lambda=1).
>
> -Justin
>
> --
> ==
>
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
>
> jalem...@outerbanks.umaryland.edu | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
>
> ==
> --
> Gromacs Users mailing list
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> * Please search the archive at
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Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

Thank you for the valuable insight. 

While on the same subject, can you give any comments on the possibility of 
using the same Free energy code in Gromacs to scale the non bonded interactions 
between protein & ligand while simultaneously doing Normal Mode analysis on the 
scaled interaction conformation to study the effect of the scaled interactions.

If its not plausible in Gromacs, can you suggest any other software.

Best Regards,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Sunday, June 11, 2017 7:01:26 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

On 6/10/17 6:15 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> Just so we are on the same page, this means that if I don't touch the 
> topology file and use the following mdp snippet, charges *are present* in the 
> topology file for the ligand group and they are automatically set to zero 
> while turning on vdW interactions (from 0 to 1) right ? Hence, there is no 
> need to manually set charges to zero (The old style of doing the 
> calculations), right?.
> 

Yes.  You can easily confirm this using energygrps between your transformed 
molecule and the rest of the system.  Coul-SR should be zero.

> Then the charges too, are turned off from 0 to 1? (1 state being the actual 
> charges present in the topology file).
> 

Charges are turned *on* if they are defined as off in the A-state (lambda=0) 
and 
on in the B-state (lambda=1).

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

Just so we are on the same page, this means that if I don't touch the topology 
file and use the following mdp snippet, charges *are present* in the topology 
file for the ligand group and they are automatically set to zero while turning 
on vdW interactions (from 0 to 1) right ? Hence, there is no need to manually 
set charges to zero (The old style of doing the calculations), right?.

Then the charges too, are turned off from 0 to 1? (1 state being the actual 
charges present in the topology file).


Thank you,

Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Saturday, June 10, 2017 5:12:25 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

On 6/8/17 6:14 PM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> I was interested in the process *prior* to the free energy change is carried 
> out, before we carry out simulations pertaining to couple-lambda0 = vdw and 
> couple-lambda1 = none. Hence, I am curious as to *how* the charges are set to 
> zero in the topology for the ligand and if is it necessary in Gromacs 5.0 
> version.
> 

You don't have to change anything in the topology.  Editing it to set charges 
to 
zero is an old style of doing these calculations.

> For the Protein-ligand system, the tutorial suggests: (for version 5.0)
> couple-lambda0  = none
> couple-lambda1  = vdw-q
> vdw_lambdas = 0.00 0.05 0.10 ... 1.00 1.00 1.00 ... 1.00
> coul_lambdas= 0.00 0.00 0.00 ... 0.00 0.05 0.10 ... 1.00
> 
> So, if this is done, is it necessary to set the charges zero in topology for 
> the ligand? If yes, can you please suggest me as to how can we do that using 
> the index file and topology file?
> 

Don't touch the topology.  Index files don't do any good here, anyway.  They're 
for selections in analysis or various groups during MD.  What the above .mdp 
settings do is turn on vdW interactions before turning on charges, which is 
necessary for stability.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I was interested in the process *prior* to the free energy change is carried 
out, before we carry out simulations pertaining to couple-lambda0 = vdw and 
couple-lambda1 = none. Hence, I am curious as to *how* the charges are set to 
zero in the topology for the ligand and if is it necessary in Gromacs 5.0 
version.

For the Protein-ligand system, the tutorial suggests: (for version 5.0)
couple-lambda0  = none
couple-lambda1  = vdw-q
vdw_lambdas = 0.00 0.05 0.10 ... 1.00 1.00 1.00 ... 1.00
coul_lambdas= 0.00 0.00 0.00 ... 0.00 0.05 0.10 ... 1.00

So, if this is done, is it necessary to set the charges zero in topology for 
the ligand? If yes, can you please suggest me as to how can we do that using 
the index file and topology file?

-Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Friday, June 9, 2017 2:40:38 AM
Subject: Re: [gmx-users] Doubt about Free Energy Calculations using g_bar

On 6/8/17 11:46 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear all,
> 
> I am attempting to find Binding affinity of a Protein-ligand system by 
> following the Free Energy tutorials 
> (http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/index.html).
> It says : "The procedure in this tutorial essentially assumes that charges 
> have been properly been turned off prior to this point". How do we turn off 
> the charges of a group specified in an index file (the ligand in my case) ?
> 

Either set them to zero in the topology or define couple-lambda0 = vdw and 
couple-lambda1 = none.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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[gmx-users] Doubt about Free Energy Calculations using g_bar

[Varvdekar Bhagyesh Rajendra]

Dear all,

I am attempting to find Binding affinity of a Protein-ligand system by 
following the Free Energy tutorials 
(http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/free_energy/index.html).
 
It says : "The procedure in this tutorial essentially assumes that charges have 
been properly been turned off prior to this point". How do we turn off the 
charges of a group specified in an index file (the ligand in my case) ?


Thanking in anticipation,

Best Regards,

Bhagyesh 
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[gmx-users] Doubt about Normal Mode Analysis while scaling nonbonded interactions

[Varvdekar Bhagyesh Rajendra]

Dear all,

Is there any way of scaling the Coulombic and/or van der Waals interactions 
between a protein-ligand system and simultaneously doing Normal Mode analysis 
on the perturbed system while scaling, perhaps using free-energy code in 
Gromacs?

Thanking in anticipation,

Best Regards,

Bhagyesh
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Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

I would like to correct myself. Actually, the COM of the two groups - Protein 
and Ligand are about 5 nm away at the end of the pulling process. But the rear 
end of the ligand is just 0.6 nm away from the closest Amino acid of the 
Protein. Is that reasonable for the Binding affinity calculations?

Best Regards,
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Friday, June 2, 2017 4:10:21 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 6/1/17 6:29 PM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> Since I have the settings pull_coord1_dim = Y Y Y, I am not sure which axis 
> the ligand is pulled. My initial simulation box size was 5 nm in each side. 
> To care of the pulling of the ligand in any direction I made the box size 14 
> in each direction filled with water. The simulation runs perfectly and ending 
> with the ligand almost 0.6 nm away from protein. But all this takes lot of 
> computation power due to the need for rigorous sampling. Is there any way to 
> cut the computation cost while maintaining the accuracy?
> 

0.6 nm is not very far, especially if your solute-box distance is 14 nm (which 
would be appropriate to get a full dissociation).  There's not much to do aside 
from making sure you're using an efficient box, e.g. rhombic dodecahedron.  A 
cube is inefficient.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

Since I have the settings pull_coord1_dim = Y Y Y, I am not sure which axis the 
ligand is pulled. My initial simulation box size was 5 nm in each side. To care 
of the pulling of the ligand in any direction I made the box size 14 in each 
direction filled with water. The simulation runs perfectly and ending with the 
ligand almost 0.6 nm away from protein. But all this takes lot of computation 
power due to the need for rigorous sampling. Is there any way to cut the 
computation cost while maintaining the accuracy?

Best Regards,
Bhagyesh

- Original Message -
From: "Varvdekar Bhagyesh Rajendra" <bhagyesh.varvde...@research.iiit.ac.in>
To: gmx-us...@gromacs.org
Sent: Thursday, June 1, 2017 7:35:16 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

Dear Justin,

Gazillion thanks for the valuable insight!

Best Regards,
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Thursday, June 1, 2017 6:13:00 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 5/31/17 10:49 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> During the pulling part of the umbrella sampling for finding binding affinity 
> of the Protien-ligand system, the ligand(peptide) is deformed and its helices 
> straighten along with large conformational changes in Protein. This is when 
> the pull_coord1_dim = Y Y Y. But when I had used pull_coord1_dim = N N Y for 
> one of the systems the peptide helices didn't deform. Is it reasonable for 
> the ligand helices to deform when finding properties like Binding affinity?
> 
> Can it be avoided if the ligand orientation is not known and using 
> pull_coord1_dim = Y Y Y is necessary.
> 

Very simply, you should be using pull_coord1_dim = Y Y Y.  That is correct.  
The 
fact that you don't see a deformation with N N Y is irrelevant and perhaps 
coincidental.

Short peptides are largely unstructured in solution, and many only acquire a 
formed secondary structure upon binding to a larger protein.  This is a well 
known phenomenon.  Spurious instability of helices is a known issue with some 
parameter sets (e.g. GROMOS96 53A6 under-stabilizes helices) but with other 
force fields partial or full unfolding is not indicative of a problem.  You 
just 
need to be sure you're adequately sampling this conformational ensemble, which 
can be expensive.

-Justin

> Best Regards,
> Bhagyesh
> 
> - Original Message -
> From: "Varvdekar Bhagyesh Rajendra" <bhagyesh.varvde...@research.iiit.ac.in>
> To: gmx-us...@gromacs.org
> Sent: Wednesday, May 31, 2017 6:42:41 PM
> Subject: Re: [gmx-users] Doubt about gmx wham analysis
> 
> Dear Justin,
> 
> Many Thanks for the swift reply and the help in answering my doubts.
> 
> Best Regards,
> Bhagyesh
> 
> - Original Message -
> From: "Justin Lemkul" <jalem...@vt.edu>
> To: gmx-us...@gromacs.org
> Sent: Wednesday, May 31, 2017 6:06:59 PM
> Subject: Re: [gmx-users] Doubt about gmx wham analysis
> 
> On 5/31/17 8:34 AM, Varvdekar Bhagyesh Rajendra wrote:
>> Dear Justin,
>>
>> In my Protein-ligand system, I have used pull_coord1_dim = Y Y Y and the 
>> ligand is pulled along the COM of two groups protein-ligand in all 
>> directions to calculate binding affinity using umbrella sampling. On the 
>> other hand, the tutorials use pull_coord1_dim = N N Y. Hence, I concluded my 
>> reaction coordinate differs as mentioned in the help menu of gmx wham : "If 
>> you have some unusual  reaction coordinate you may also generate your own 
>> .pdo files and feed them with the -ip option into to gmx wham"
>>
> 
> The fact that your reaction coordinate is different from the tutorial is
> irrelevant.  You have an absolutely normal reaction coordinate and does not
> apply to what the gmx wham help text is talking about (which is probably a 
> very
> outdated note at this point, given the massive changes in the pull code in
> recent versions).
> 
>> Also, the following warning is thrown by gmx wham: " WARNING, no data point 
>> in bin 7 (z=0.403502) ! You may not get a reasonable profile. Check your 
>> histograms! "
>> I was not sure if the z corresponds to the coordinate axis or just the 
>> z-axis (which was not the only reaction coordinate in my system).
>>
> 
> It is the length along zeta, the reaction coordinate.  Don't confuse it with 
> the
> z-axis, it's just shorthand.
> 
>> All this made me conclude that the pullx files are not enough and the so 
>> called pdo files must be necessary, hence the doubt arised. I would 
>> appreciate if some more light is shed in this area.
>>
> 
> You need

Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

Gazillion thanks for the valuable insight!

Best Regards,
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Thursday, June 1, 2017 6:13:00 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 5/31/17 10:49 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> During the pulling part of the umbrella sampling for finding binding affinity 
> of the Protien-ligand system, the ligand(peptide) is deformed and its helices 
> straighten along with large conformational changes in Protein. This is when 
> the pull_coord1_dim = Y Y Y. But when I had used pull_coord1_dim = N N Y for 
> one of the systems the peptide helices didn't deform. Is it reasonable for 
> the ligand helices to deform when finding properties like Binding affinity?
> 
> Can it be avoided if the ligand orientation is not known and using 
> pull_coord1_dim = Y Y Y is necessary.
> 

Very simply, you should be using pull_coord1_dim = Y Y Y.  That is correct.  
The 
fact that you don't see a deformation with N N Y is irrelevant and perhaps 
coincidental.

Short peptides are largely unstructured in solution, and many only acquire a 
formed secondary structure upon binding to a larger protein.  This is a well 
known phenomenon.  Spurious instability of helices is a known issue with some 
parameter sets (e.g. GROMOS96 53A6 under-stabilizes helices) but with other 
force fields partial or full unfolding is not indicative of a problem.  You 
just 
need to be sure you're adequately sampling this conformational ensemble, which 
can be expensive.

-Justin

> Best Regards,
> Bhagyesh
> 
> - Original Message -
> From: "Varvdekar Bhagyesh Rajendra" <bhagyesh.varvde...@research.iiit.ac.in>
> To: gmx-us...@gromacs.org
> Sent: Wednesday, May 31, 2017 6:42:41 PM
> Subject: Re: [gmx-users] Doubt about gmx wham analysis
> 
> Dear Justin,
> 
> Many Thanks for the swift reply and the help in answering my doubts.
> 
> Best Regards,
> Bhagyesh
> 
> - Original Message -
> From: "Justin Lemkul" <jalem...@vt.edu>
> To: gmx-us...@gromacs.org
> Sent: Wednesday, May 31, 2017 6:06:59 PM
> Subject: Re: [gmx-users] Doubt about gmx wham analysis
> 
> On 5/31/17 8:34 AM, Varvdekar Bhagyesh Rajendra wrote:
>> Dear Justin,
>>
>> In my Protein-ligand system, I have used pull_coord1_dim = Y Y Y and the 
>> ligand is pulled along the COM of two groups protein-ligand in all 
>> directions to calculate binding affinity using umbrella sampling. On the 
>> other hand, the tutorials use pull_coord1_dim = N N Y. Hence, I concluded my 
>> reaction coordinate differs as mentioned in the help menu of gmx wham : "If 
>> you have some unusual  reaction coordinate you may also generate your own 
>> .pdo files and feed them with the -ip option into to gmx wham"
>>
> 
> The fact that your reaction coordinate is different from the tutorial is
> irrelevant.  You have an absolutely normal reaction coordinate and does not
> apply to what the gmx wham help text is talking about (which is probably a 
> very
> outdated note at this point, given the massive changes in the pull code in
> recent versions).
> 
>> Also, the following warning is thrown by gmx wham: " WARNING, no data point 
>> in bin 7 (z=0.403502) ! You may not get a reasonable profile. Check your 
>> histograms! "
>> I was not sure if the z corresponds to the coordinate axis or just the 
>> z-axis (which was not the only reaction coordinate in my system).
>>
> 
> It is the length along zeta, the reaction coordinate.  Don't confuse it with 
> the
> z-axis, it's just shorthand.
> 
>> All this made me conclude that the pullx files are not enough and the so 
>> called pdo files must be necessary, hence the doubt arised. I would 
>> appreciate if some more light is shed in this area.
>>
> 
> You need better sampling, not archaic file formats.
> 
> -Justin
> 

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

During the pulling part of the umbrella sampling for finding binding affinity 
of the Protien-ligand system, the ligand(peptide) is deformed and its helices 
straighten along with large conformational changes in Protein. This is when the 
pull_coord1_dim = Y Y Y. But when I had used pull_coord1_dim = N N Y for one of 
the systems the peptide helices didn't deform. Is it reasonable for the ligand 
helices to deform when finding properties like Binding affinity? 

Can it be avoided if the ligand orientation is not known and using 
pull_coord1_dim = Y Y Y is necessary.

Best Regards,
Bhagyesh

- Original Message -
From: "Varvdekar Bhagyesh Rajendra" <bhagyesh.varvde...@research.iiit.ac.in>
To: gmx-us...@gromacs.org
Sent: Wednesday, May 31, 2017 6:42:41 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

Dear Justin,

Many Thanks for the swift reply and the help in answering my doubts.

Best Regards,
Bhagyesh  

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, May 31, 2017 6:06:59 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 5/31/17 8:34 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> In my Protein-ligand system, I have used pull_coord1_dim = Y Y Y and the 
> ligand is pulled along the COM of two groups protein-ligand in all directions 
> to calculate binding affinity using umbrella sampling. On the other hand, the 
> tutorials use pull_coord1_dim = N N Y. Hence, I concluded my reaction 
> coordinate differs as mentioned in the help menu of gmx wham : "If you have 
> some unusual  reaction coordinate you may also generate your own .pdo files 
> and feed them with the -ip option into to gmx wham"
> 

The fact that your reaction coordinate is different from the tutorial is 
irrelevant.  You have an absolutely normal reaction coordinate and does not 
apply to what the gmx wham help text is talking about (which is probably a very 
outdated note at this point, given the massive changes in the pull code in 
recent versions).

> Also, the following warning is thrown by gmx wham: " WARNING, no data point 
> in bin 7 (z=0.403502) ! You may not get a reasonable profile. Check your 
> histograms! "
> I was not sure if the z corresponds to the coordinate axis or just the z-axis 
> (which was not the only reaction coordinate in my system).
> 

It is the length along zeta, the reaction coordinate.  Don't confuse it with 
the 
z-axis, it's just shorthand.

> All this made me conclude that the pullx files are not enough and the so 
> called pdo files must be necessary, hence the doubt arised. I would 
> appreciate if some more light is shed in this area.
> 

You need better sampling, not archaic file formats.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

Many Thanks for the swift reply and the help in answering my doubts.

Best Regards,
Bhagyesh  

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, May 31, 2017 6:06:59 PM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 5/31/17 8:34 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear Justin,
> 
> In my Protein-ligand system, I have used pull_coord1_dim = Y Y Y and the 
> ligand is pulled along the COM of two groups protein-ligand in all directions 
> to calculate binding affinity using umbrella sampling. On the other hand, the 
> tutorials use pull_coord1_dim = N N Y. Hence, I concluded my reaction 
> coordinate differs as mentioned in the help menu of gmx wham : "If you have 
> some unusual  reaction coordinate you may also generate your own .pdo files 
> and feed them with the -ip option into to gmx wham"
> 

The fact that your reaction coordinate is different from the tutorial is 
irrelevant.  You have an absolutely normal reaction coordinate and does not 
apply to what the gmx wham help text is talking about (which is probably a very 
outdated note at this point, given the massive changes in the pull code in 
recent versions).

> Also, the following warning is thrown by gmx wham: " WARNING, no data point 
> in bin 7 (z=0.403502) ! You may not get a reasonable profile. Check your 
> histograms! "
> I was not sure if the z corresponds to the coordinate axis or just the z-axis 
> (which was not the only reaction coordinate in my system).
> 

It is the length along zeta, the reaction coordinate.  Don't confuse it with 
the 
z-axis, it's just shorthand.

> All this made me conclude that the pullx files are not enough and the so 
> called pdo files must be necessary, hence the doubt arised. I would 
> appreciate if some more light is shed in this area.
> 

You need better sampling, not archaic file formats.

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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Re: [gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear Justin,

In my Protein-ligand system, I have used pull_coord1_dim = Y Y Y and the ligand 
is pulled along the COM of two groups protein-ligand in all directions to 
calculate binding affinity using umbrella sampling. On the other hand, the 
tutorials use pull_coord1_dim = N N Y. Hence, I concluded my reaction 
coordinate differs as mentioned in the help menu of gmx wham : "If you have 
some unusual  reaction coordinate you may also generate your own .pdo files and 
feed them with the -ip option into to gmx wham"

Also, the following warning is thrown by gmx wham: " WARNING, no data point in 
bin 7 (z=0.403502) ! You may not get a reasonable profile. Check your 
histograms! "
I was not sure if the z corresponds to the coordinate axis or just the z-axis 
(which was not the only reaction coordinate in my system).

All this made me conclude that the pullx files are not enough and the so called 
pdo files must be necessary, hence the doubt arised. I would appreciate if some 
more light is shed in this area.

Thank you for the help in answering the doubt.

Best Regards,
Bhagyesh

- Original Message -
From: "Justin Lemkul" <jalem...@vt.edu>
To: gmx-us...@gromacs.org
Sent: Wednesday, May 31, 2017 5:42:52 AM
Subject: Re: [gmx-users] Doubt about gmx wham analysis

On 5/30/17 6:49 AM, Varvdekar Bhagyesh Rajendra wrote:
> Dear all,
> 
> I have followed the Umbrella sampling tutorial 
> (http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html)
>  on a Protein-ligand system using gromacs 5.1.1 while making some changes in 
> md_pull code with pull_coord1_dim = Y Y Y . Now I have to perform WHAM 
> analysis using gmx wham. As my system (Protein-ligand system) has the 
> reaction coordinate as the center of masses between the protein and ligand I 
> have to supply the .pdo file as suggested in gmx wham help menu. I would 
> appreciate if anyone could help me to generate these pdo files because I have 
> not encountered any option to generate them.
> 

.pdo files were umbrella sampling output files from ancient versions of 
GROMACS. 
  Support for their interpretation is maintained only for backwards 
compatibility.

Look through the tutorial again; nowhere does it use .pdo files and yet it 
still 
calculates a PMF :)

-Justin

-- 
==

Justin A. Lemkul, Ph.D.
Ruth L. Kirschstein NRSA Postdoctoral Fellow

Department of Pharmaceutical Sciences
School of Pharmacy
Health Sciences Facility II, Room 629
University of Maryland, Baltimore
20 Penn St.
Baltimore, MD 21201

jalem...@outerbanks.umaryland.edu | (410) 706-7441
http://mackerell.umaryland.edu/~jalemkul

==
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[gmx-users] Doubt about constrained NM

[Varvdekar Bhagyesh Rajendra]

Dear all,

Is it possible to do constrained Normal Mode Analysis in Gromacs such as a free 
ligand buried in a constrained protein to study the effects of the binding on 
the normal modes of ligand? I had tried to used DPOSRES_A, as my protein is 
chain A, but everytime gromacs throws the error "Constraints present with 
Normal Mode Analysis, this combination is not supported". 

If indeed it is posssible, what are the suggested settings to be done in mdp 
file. If no, what are the suggested softwares that can do the same.

Thank you,

Best Regards,

Bhagyesh 
IIIT Hyderabad, India
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[gmx-users] Doubt about gmx wham analysis

[Varvdekar Bhagyesh Rajendra]

Dear all,

I have followed the Umbrella sampling tutorial 
(http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/umbrella/index.html)
 on a Protein-ligand system using gromacs 5.1.1 while making some changes in 
md_pull code with pull_coord1_dim = Y Y Y . Now I have to perform WHAM analysis 
using gmx wham. As my system (Protein-ligand system) has the reaction 
coordinate as the center of masses between the protein and ligand I have to 
supply the .pdo file as suggested in gmx wham help menu. I would appreciate if 
anyone could help me to generate these pdo files because I have not encountered 
any option to generate them.

Thanking in anticipation,
Bhagyesh 
IIIT Hyderabad, India
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Re: [gmx-users] Doubts about g_lie and g_bar

[Varvdekar Bhagyesh Rajendra]

Hi Mark,

Thank you for replying.
I would be grateful if you could please answer the doubts I have asked in my 
previous emails.

Thank you,
Bhagyesh

- Original Message -
From: "Mark Abraham" <mark.j.abra...@gmail.com>
To: gmx-us...@gromacs.org
Sent: Monday, May 15, 2017 7:25:43 PM
Subject: Re: [gmx-users] Doubts about g_lie and g_bar

Hi,

On Sat, May 13, 2017 at 5:18 PM Varvdekar Bhagyesh Rajendra <
bhagyesh.varvde...@research.iiit.ac.in> wrote:

> Dear all,
>
> I have tried to find Delta G of Binding using g_lie and g_bar from the
> following systems (Protein+Ligand with ligand = chain B):
> PDB Ids: 1CDL, 1CKK, 1NIW, 2L7L, 2o60.
>
> I have encountered following 2 doubts while doing so:
>
> 1. This doubt may have been answered in the past threads but I couldn't
> find a precise answer for it. So, I would appreciate if this is answered
> here again in more details. I have used PME in the production runs of my
> systems for finding Delta G_Binding using g_lie. But many threads on
> Gromacs forum warn against it and advise to rerun the whole trajectory
> using Reaction field Zero, but the cutoff for this rerun is not clearly
> given. Some threads say a cutoff with large cutoff using RF-0 is necessary.
> Can anyone please answer as to what cutoff(Relative to the system) should
> be given while re-running the trajectory and what all changes have to be
> done in the original mdp file(which uses PME). Also, a brief explanation
> for the whole process for the need of the re-run would be beneficial.
> Following are the changes I made after studying the past threads:
>
> 
> ;; With PME  ;;; | ;; Re-Run without
> PME ;;
>
> -
>  ; Neighborsearching |  ; Neighborsearching
>   ns_type = grid  ; search neighboring grid  |  ns_type =
> grid  ; search neighboring grid cells
>   nstlist = 5 ; 10 fs|  nstlist = 5
>  ; 10 fs
>   rlist   = 0.9   ; short-range neighborlist |  rlist   = 1.2
>  ; short-range neighborlist cutoff (nm)
>   rcoulomb= 0.9   ; short-range electrostatic|  rcoulomb= 0.9
>  ; short-range electrostatic cutoff (in nm)
>   rvdw= 1.4   ; short-range van der Waals|  rvdw= 1.4
>  ; short-range van der Waals cutoff (in nm)
>  |
> ; Electrostatics | ; Electrostatics
> coulombtype = PME| coulombtype  =
> Reaction-Field-zero
>  | epsilon_rf  =  0
>
> ---
>

IMO these choices should follow from your understanding of the method that
you are implementing, e.g. as reported in peer-reviewed publications, not
just mailing list threads or tutorials. That way you have some confirmation
that the method was thought reasonable, and produced some kind of result.

2. Free Energy tutorials of Gromacs suggest using oriental restraints
> and/or distance restraints on protein-ligand systems for calculating Delta
> G_Binding using g_bar. But the exact details are not given on the website.
> One can see that in my systems the protein is fully surrounding the ligand
> except two entrances. So, I ask if distance and/or oriental constraint is
> necessary to keep from floating it away. If yes, can anyone suggest some
> simple ways for doing so in Gromacs. I found some research papers who
> employ gruesome techiques of finding the correct atoms to constraint in the
> ligand (for eg.Theoretical Study of the Binding Profile of the Allosteric
> Modulator NS-1738 with a Chimera Structure of the α 7 Nicotinic
> Acetylcholine Receptor).
>

The [intermolecular_interactions] directive introduced in recent GROMACS
versions is useful for such restraints, ie. when you want to refer to atoms
in different [moleculetypes], and can do so with global atom numbers.

Mark

I would be grateful if you could answer the above doubts.
>
> Thanking you in anticipation,
>
> Best Regards,
>
> Bhagyesh Varvdekar,
> Undergrad student,
> IIIT Hyderabad, India.
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> Gromacs Users mailing list
>
> * Please search the archive at
> http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before
> posting!
>
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>
> * For (un)subscribe req

[gmx-users] Doubts about g_lie and g_bar

[Varvdekar Bhagyesh Rajendra]

Dear all,

I have tried to find Delta G of Binding using g_lie and g_bar from the 
following systems (Protein+Ligand with ligand = chain B):
PDB Ids: 1CDL, 1CKK, 1NIW, 2L7L, 2o60.

I have encountered following 2 doubts while doing so:

1. This doubt may have been answered in the past threads but I couldn't find a 
precise answer for it. So, I would appreciate if this is answered here again in 
more details. I have used PME in the production runs of my systems for finding 
Delta G_Binding using g_lie. But many threads on Gromacs forum warn against it 
and advise to rerun the whole trajectory using Reaction field Zero, but the 
cutoff for this rerun is not clearly given. Some threads say a cutoff with 
large cutoff using RF-0 is necessary. Can anyone please answer as to what 
cutoff(Relative to the system) should be given while re-running the trajectory 
and what all changes have to be done in the original mdp file(which uses PME). 
Also, a brief explanation for the whole process for the need of the re-run 
would be beneficial. Following are the changes I made after studying the past 
threads:

;; With PME  ;;; | ;; Re-Run without PME ;;
-
 ; Neighborsearching |  ; Neighborsearching
  ns_type = grid  ; search neighboring grid  |  ns_type = grid  
; search neighboring grid cells
  nstlist = 5 ; 10 fs|  nstlist = 5 
; 10 fs
  rlist   = 0.9   ; short-range neighborlist |  rlist   = 1.2   
; short-range neighborlist cutoff (nm)  
  
  rcoulomb= 0.9   ; short-range electrostatic|  rcoulomb= 0.9   
; short-range electrostatic cutoff (in nm)
  rvdw= 1.4   ; short-range van der Waals|  rvdw= 1.4   
; short-range van der Waals cutoff (in nm)
 |
; Electrostatics | ; Electrostatics
coulombtype = PME| coulombtype  =  
Reaction-Field-zero 
 | epsilon_rf  =  0
---

2. Free Energy tutorials of Gromacs suggest using oriental restraints and/or 
distance restraints on protein-ligand systems for calculating Delta G_Binding 
using g_bar. But the exact details are not given on the website. One can see 
that in my systems the protein is fully surrounding the ligand except two 
entrances. So, I ask if distance and/or oriental constraint is necessary to 
keep from floating it away. If yes, can anyone suggest some simple ways for 
doing so in Gromacs. I found some research papers who employ gruesome techiques 
of finding the correct atoms to constraint in the ligand (for eg.Theoretical 
Study of the Binding Profile of the Allosteric Modulator NS-1738 with a Chimera 
Structure of the α 7 Nicotinic Acetylcholine Receptor).

I would be grateful if you could answer the above doubts.

Thanking you in anticipation,

Best Regards,

Bhagyesh Varvdekar, 
Undergrad student,
IIIT Hyderabad, India.
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[gmx-users] Doubts about g_lie and g_bar

[Varvdekar Bhagyesh Rajendra]

Dear all,

I have tried to find Delta G of Binding using g_lie and g_bar from the 
following systems (Protein+Ligand with ligand = chain B):
PDB Ids: 1CDL, 1CKK, 1NIW, 2L7L, 2o60.

I have encountered following 2 doubts while doing so:

1. This doubt may have been answered in the past threads but I couldn't find a 
precise answer for it. So, I would appreciate if this is answered here again in 
more details. I have used PME in the production runs of my systems for finding 
Delta G_Binding using g_lie. But many threads on Gromacs forum warn against it 
and advise to rerun the whole trajectory using Reaction field Zero, but the 
cutoff for this rerun is not clearly given. Some threads say a cutoff with 
large cutoff using RF-0 is necessary. Can anyone please answer as to what 
cutoff(Relative to the system) should be given while re-running the trajectory 
and what all changes have to be done in the original mdp file(which uses PME). 
Also, a brief explanation for the whole process for the need of the re-run 
would be beneficial. Following are the changes I made after studying the past 
threads:

;; With PME  ;;; | ;; Re-Run without PME ;;
-
 ; Neighborsearching |  ; Neighborsearching
  ns_type = grid  ; search neighboring grid  |  ns_type = grid  
; search neighboring grid cells
  nstlist = 5 ; 10 fs|  nstlist = 5 
; 10 fs
  rlist   = 0.9   ; short-range neighborlist |  rlist   = 1.2   
; short-range neighborlist cutoff (nm)  
  
  rcoulomb= 0.9   ; short-range electrostatic|  rcoulomb= 0.9   
; short-range electrostatic cutoff (in nm)
  rvdw= 1.4   ; short-range van der Waals|  rvdw= 1.4   
; short-range van der Waals cutoff (in nm)
 |
; Electrostatics | ; Electrostatics
coulombtype = PME| coulombtype  =  
Reaction-Field-zero 
 | epsilon_rf  =  0
---

2. Free Energy tutorials of Gromacs suggest using oriental restraints and/or 
distance restraints on protein-ligand systems for calculating Delta G_Binding 
using g_bar. But the exact details are not given on the website. One can see 
that in my systems the protein is fully surrounding the ligand except two 
entrances. So, I ask if distance and/or oriental constraint is necessary to 
keep from floating it away. If yes, can anyone suggest some simple ways for 
doing so in Gromacs. I found some research papers who employ gruesome techiques 
of finding the correct atoms to constraint in the ligand (for eg.Theoretical 
Study of the Binding Profile of the Allosteric Modulator NS-1738 with a Chimera 
Structure of the α 7 Nicotinic Acetylcholine Receptor).

I would be grateful if you could answer the above doubts.

Thanking you in anticipation,

Best Regards,

Bhagyesh Varvdekar, 
Undergrad student,
IIIT Hyderabad, India.
-- 
Gromacs Users mailing list

* Please search the archive at 
http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting!

* Can't post? Read http://www.gromacs.org/Support/Mailing_Lists

* For (un)subscribe requests visit
https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a 
mail to gmx-users-requ...@gromacs.org.