Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

On Thu, 2 Jun 2016 08:27:15 +
"Nash, Anthony"  wrote:

> Dear Hannes,
> 
> Thanks for all the help yesterday, it helped. I, hopefully, have just
> the one final question.
> 
> I am still a little confused how Gromacs deals with the interactions
> (vdW & Coul) with the environment when a soft-core potential has been
> used to switch between molecules (typeA and typeB in the topology
> file). I understand how lambda can be used to 1) phase out the charge
> then 2) phase out the vdW interactions for a molecule that is
> disappearing (or reverse for appearing) to capture hydration
> energetics e.g., Justin¹s methane in water FE tutorial. 
> 
> However, in the case of a D2K (aspartic-acid to lysine)
> dual-topology

How is your setup dual-topolgy?  http://dx.doi.org/10.1002/jcc.23804
indicates to me that the pmx approach seems to go for as much single
topology as possible.  Your case seems to fall into this particular
category.


> how are the vdW and charges brought back into play for
> typeB, when the interactions of typeA have been coupled to lambda as
> per your example below? 

In a second setup as explained earlier, assuming you want to separate
vdW from Coulomb.  See attachment for an unrelated example system.
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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

Dear Hannes,

Thanks for all the help yesterday, it helped. I, hopefully, have just the
one final question.

I am still a little confused how Gromacs deals with the interactions (vdW
& Coul) with the environment when a soft-core potential has been used to
switch between molecules (typeA and typeB in the topology file). I
understand how lambda can be used to 1) phase out the charge then 2) phase
out the vdW interactions for a molecule that is disappearing (or reverse
for appearing) to capture hydration energetics e.g., Justin¹s methane in
water FE tutorial. 

However, in the case of a D2K (aspartic-acid to lysine) dual-topology, how
are the vdW and charges brought back into play for typeB, when the
interactions of typeA have been coupled to lambda as per your example
below? 

fep-lambdas = 0.0 0.2 0.4 0.6 0.8 1.0  1.0  1.0  etc.
vdw-lambdas = 0.0 0.0 0.0 0.0 0.0 0.0  0.05 0.10 etc.
mass-lambdas as above

I apologise if I may have misunderstood one of your earlier explanations,
I think this is the only piece of the puzzle left for me to understand.

Many thanks
Anthony



On 01/06/2016 19:04, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Hannes Loeffler"
 wrote:

>On Wed, 1 Jun 2016 16:15:31 +
>"Nash, Anthony"  wrote:
>
>> In the mean while, do you know of any tutorials (besides the methane
>> in water FE tutorial) regarding TI for amino acid substitution?
>
>I am not aware of one.  You could try
>http://www.alchemistry.org/
>
>
>> And by ³q_off² and ³vdw_on/off², I assume you are referring to the
>> Œvalue¹ of the couple-lambda0: parameter?
>
>No.  I'm referring to the respective lambda paths.
>
>
>Cheers,
>Hannes.
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Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

On Wed, 1 Jun 2016 16:15:31 +
"Nash, Anthony"  wrote:

> In the mean while, do you know of any tutorials (besides the methane
> in water FE tutorial) regarding TI for amino acid substitution? 

I am not aware of one.  You could try
http://www.alchemistry.org/


> And by “q_off” and “vdw_on/off”, I assume you are referring to the
> ‘value’ of the couple-lambda0: parameter?

No.  I'm referring to the respective lambda paths.


Cheers,
Hannes.
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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

In the mean while, do you know of any tutorials (besides the methane in
water FE tutorial) regarding TI for amino acid substitution? And by
“q_off” and “vdw_on/off”, I assume you are referring to the ‘value’ of the
couple-lambda0: parameter?

Thanks
Anthony

Dr Anthony Nash
Department of Chemistry
University College London





On 01/06/2016 16:55, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Nash, Anthony"
 wrote:

>Thanks for all of this material. I’ll take some time and digest what
>you’ve said. 
>
>No doubt I’ll have a few more questions tomorrow ;-)
>
>Thanks
>Anthony 
>
>
>On 01/06/2016 16:38, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
>behalf of Hannes Loeffler"
>hannes.loeff...@stfc.ac.uk> wrote:
>
>>On Wed, 1 Jun 2016 15:00:51 +
>>"Nash, Anthony"  wrote:
>>
>>> >  This also assumes that
>>> >you have vanishing atoms only.  If you have appearing atoms only you
>>> >would obviously have to revers the order, and when you have both you
>>> >will have to run with two mdp/tpr setups.
>>> 
>>> 
>>> With aspartic acid transforming into lysine on one polypeptide chain
>>> and then lysine transforming into aspartic acid polypeptide chain,
>>> all in the same system (keeps the charges the same and is a complete
>>> thermodynamic cycle), I will have both appearing and disappearing
>>> atoms. How do you mean ³to run with two mdp/tpr setups²? Is there an
>>> example you could give (which I am grateful for) or one in the manual?
>>
>>Lambda paths are not selective in the sense that you could apply them
>>to only a subset of the system.  So if you have both disappearing and
>>appearing atoms you have to:
>>1) turn off the charges on the disappearing group (or alternatively all
>>charges to avoid a charged total system), q_off
>>2) turn off the vdW parameters for the disappearing group, vdw_off
>>3) turn on the vdW parameters for the appearing group, vdw_on
>>4) turn on the charges of the appearing group (or all charges), q_on
>>
>>If you try to do this with Gromacs you will realise that the best you
>>can do is combine this into 2 mdp steps: 1) q_off and vdw_on/off and 2)
>>q_on.  Alternatively you can combine the vdw bit with 2) but that
>>doesn't make any difference.  Of course, if you could assume that a
>>combined Coulomb/vdW transformation will work, this would be a
>>non-issue...
>>
>>Also, I wonder how pmx maps aspartate onto lysine.  I would think that
>>the gamma-carboxylate should not map onto the gamma-methylene but
>>rather the residue should be branched off at the C-beta and so
>>duplicate the rest of the residue.
>>-- 
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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

Thanks for all of this material. I’ll take some time and digest what
you’ve said. 

No doubt I’ll have a few more questions tomorrow ;-)

Thanks
Anthony 


On 01/06/2016 16:38, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Hannes Loeffler"
 wrote:

>On Wed, 1 Jun 2016 15:00:51 +
>"Nash, Anthony"  wrote:
>
>> >  This also assumes that
>> >you have vanishing atoms only.  If you have appearing atoms only you
>> >would obviously have to revers the order, and when you have both you
>> >will have to run with two mdp/tpr setups.
>> 
>> 
>> With aspartic acid transforming into lysine on one polypeptide chain
>> and then lysine transforming into aspartic acid polypeptide chain,
>> all in the same system (keeps the charges the same and is a complete
>> thermodynamic cycle), I will have both appearing and disappearing
>> atoms. How do you mean ³to run with two mdp/tpr setups²? Is there an
>> example you could give (which I am grateful for) or one in the manual?
>
>Lambda paths are not selective in the sense that you could apply them
>to only a subset of the system.  So if you have both disappearing and
>appearing atoms you have to:
>1) turn off the charges on the disappearing group (or alternatively all
>charges to avoid a charged total system), q_off
>2) turn off the vdW parameters for the disappearing group, vdw_off
>3) turn on the vdW parameters for the appearing group, vdw_on
>4) turn on the charges of the appearing group (or all charges), q_on
>
>If you try to do this with Gromacs you will realise that the best you
>can do is combine this into 2 mdp steps: 1) q_off and vdw_on/off and 2)
>q_on.  Alternatively you can combine the vdw bit with 2) but that
>doesn't make any difference.  Of course, if you could assume that a
>combined Coulomb/vdW transformation will work, this would be a
>non-issue...
>
>Also, I wonder how pmx maps aspartate onto lysine.  I would think that
>the gamma-carboxylate should not map onto the gamma-methylene but
>rather the residue should be branched off at the C-beta and so
>duplicate the rest of the residue.
>-- 
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Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

On Wed, 1 Jun 2016 15:00:51 +
"Nash, Anthony"  wrote:

> >  This also assumes that
> >you have vanishing atoms only.  If you have appearing atoms only you
> >would obviously have to revers the order, and when you have both you
> >will have to run with two mdp/tpr setups.
> 
> 
> With aspartic acid transforming into lysine on one polypeptide chain
> and then lysine transforming into aspartic acid polypeptide chain,
> all in the same system (keeps the charges the same and is a complete
> thermodynamic cycle), I will have both appearing and disappearing
> atoms. How do you mean ³to run with two mdp/tpr setups²? Is there an
> example you could give (which I am grateful for) or one in the manual?

Lambda paths are not selective in the sense that you could apply them
to only a subset of the system.  So if you have both disappearing and
appearing atoms you have to:
1) turn off the charges on the disappearing group (or alternatively all
charges to avoid a charged total system), q_off
2) turn off the vdW parameters for the disappearing group, vdw_off
3) turn on the vdW parameters for the appearing group, vdw_on
4) turn on the charges of the appearing group (or all charges), q_on

If you try to do this with Gromacs you will realise that the best you
can do is combine this into 2 mdp steps: 1) q_off and vdw_on/off and 2)
q_on.  Alternatively you can combine the vdw bit with 2) but that
doesn't make any difference.  Of course, if you could assume that a
combined Coulomb/vdW transformation will work, this would be a
non-issue...

Also, I wonder how pmx maps aspartate onto lysine.  I would think that
the gamma-carboxylate should not map onto the gamma-methylene but
rather the residue should be branched off at the C-beta and so
duplicate the rest of the residue.
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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

Dear Hannes, please see my comment below..


On 01/06/2016 14:45, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Hannes Loeffler"
 wrote:

>On Wed, 1 Jun 2016 12:06:20 +
>"Nash, Anthony"  wrote:
>
>> 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
>> mass_lambdas = 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
>> 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
>> fep_lambdas =  0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6
>> 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0
>
>This will transform both vdW _and_ Coulomb terms at the same time but
>at a different pace.  Maybe you want something like
>
>fep-lambdas = 0.0 0.2 0.4 0.6 0.8 1.0  1.0  1.0  etc.
>vdw-lambdas = 0.0 0.0 0.0 0.0 0.0 0.0  0.05 0.10 etc.
>mass-lambdas as above
>
>This will first transform Coulomb and bonded terms in the first six
>lambdas and vdW from the 7th lambda onwards.


That is beginning to make perfect sense now. Many thanks for that help.



>  This also assumes that
>you have vanishing atoms only.  If you have appearing atoms only you
>would obviously have to revers the order, and when you have both you
>will have to run with two mdp/tpr setups.


With aspartic acid transforming into lysine on one polypeptide chain and
then lysine transforming into aspartic acid polypeptide chain, all in the
same system (keeps the charges the same and is a complete thermodynamic
cycle), I will have both appearing and disappearing atoms. How do you mean
³to run with two mdp/tpr setups²? Is there an example you could give
(which I am grateful for) or one in the manual?


>> couple-moltype   = protein
>> couple-lambda0   = vdw-q
>> couple-lambda1   = vdw-q
>
>This will decouple all atoms in the 'protein' selection from the
>environment.  This is for absolute transformation and not what you seem
>to want to do i.e. a relative transformation of one residue into
>another.  So avoid those parameters.

Thanks for that information.


Many thanks
Anthony

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Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

On Wed, 1 Jun 2016 12:06:20 +
"Nash, Anthony"  wrote:

> 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
> mass_lambdas = 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
> 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
> fep_lambdas =  0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6
> 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0

This will transform both vdW _and_ Coulomb terms at the same time but
at a different pace.  Maybe you want something like

fep-lambdas = 0.0 0.2 0.4 0.6 0.8 1.0  1.0  1.0  etc.
vdw-lambdas = 0.0 0.0 0.0 0.0 0.0 0.0  0.05 0.10 etc.
mass-lambdas as above

This will first transform Coulomb and bonded terms in the first six
lambdas and vdW from the 7th lambda onwards.  This also assumes that
you have vanishing atoms only.  If you have appearing atoms only you
would obviously have to revers the order, and when you have both you
will have to run with two mdp/tpr setups.


> couple-moltype   = protein
> couple-lambda0   = vdw-q
> couple-lambda1   = vdw-q

This will decouple all atoms in the 'protein' selection from the
environment.  This is for absolute transformation and not what you seem
to want to do i.e. a relative transformation of one residue into
another.  So avoid those parameters.
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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

Hi Hannes,

Thanks for the reply. At the moment for a change in single amino acid in a
triplet (a pair of triplets, showing forward and reverse change) I am
settling with:

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
mass_lambdas = 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0 0.0 0.0
fep_lambdas =  0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7
0.8 0.8 0.9 0.9 1.0 1.0


free_energy  = yes
init_lambda_state= 0
delta_lambda = 0
calc_lambda_neighbors= 1; only immediate neighboring windows


; Options for the decoupling
sc-alpha = 0.5
sc-coul  = yes
sc-power = 1.0
sc-sigma = 0.3
couple-moltype   = protein
couple-lambda0   = vdw-q
couple-lambda1   = vdw-q
couple-intramol  = no
nstdhdl  = 10



The  mass will be conserved (it is a full cycle in one system). Everything
else scales with feb_lambdas apart from vdw which will (I am guessing)
require more sampling. This is my first attempt, I don't expect to get a
true understanding of it yet :-)

Thanks again
Anthony





On 01/06/2016 12:43, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Hannes Loeffler"
 wrote:

>
>Set the vector to all-zeroes (or ones).
>
>
>On Wed, 1 Jun 2016 09:47:59 +
>"Nash, Anthony"  wrote:
>
>> Hi Hannes,
>> 
>> 
>> Many thanks for the reply. With regards to your final comment I
>> understand conserving mass in theory, but I am a little confused
>> regarding, "keep the mass-lambdas at one end-point as they can
>> interact badly with constraints". I am testing pmx on a two-molecule
>> one-system I.e., G-D2K-G and G-K2D-G in the same system. How ought I
>> define the mass-lambdas for this system? (nothing accurate, just an
>> example would be great)?
>> 
>> Thanks
>> Anthony
>> 
>> 
>> On 01/06/2016 09:55,
>> "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on behalf of
>> Hannes Loeffler" > on behalf of hannes.loeff...@stfc.ac.uk> wrote:
>> 
>> >On Wed, 1 Jun 2016 07:54:56 +
>> >"Nash, Anthony"  wrote:
>> >
>> >> In the tutorial, charges are off in the topology and the
>> >> electrostatic coupling to lambda remains 0 throughout the 20
>> >> windows. I assume setting col_lambdas=0 0 0 Š was for that very
>> >> reason I.e., the charges were off? Could the charges not have been
>> >> left on and col_lambdas defined similar to vdw_lambdas?
>> >> (I understand that if charges remain constant, as vdw turns off,
>> >> the system will probably blow up as attraction brings molecules
>> >> infinitely close).
>> >
>> >Technically, Gromacs allows you to vary both vdW and Coulomb lambdas
>> >simultaneously because Gromacs can apply softcore potentials to both.
>> >In practice though it seems that many workers still prefer to
>> >separate the two terms from each other.
>> >
>> > 
>> >> If my transition is from a small molecule into a small molecule
>> >> e.g., G-D-G to G-K-D, (the PMX paper) should I define all three
>> >> lambdas: vdw_lambdas, col_lambdas and bonds_lambdas? Between
>> >> states A and B, VdW, charges and bonds are all changing.
>> >
>> >Lambda paths are only about separating the various force field terms
>> >from each other.  If you do not explicitly state any of those lambda
>> >vectors they will adopt they same lambdas as specified in
>> >fep-lambdas, see manual.  I do not see a reason why you would want
>> >to separate out the bonded terms as well.  They are subject to a
>> >linear transformation only anyway.
>> >
>> >What you may want to do is to keep the mass-lambdas at one end-point
>> >as they can interact badly with constraints.  In a proper
>> >thermodynamic cycle mass contributions must perfectly cancel.
>> >
>> >
>> >Cheers,
>> >Hannes.
>> >-- 
>> >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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>> >send a mail to gmx-users-requ...@gromacs.org.
>> 
>
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Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

Set the vector to all-zeroes (or ones).


On Wed, 1 Jun 2016 09:47:59 +
"Nash, Anthony"  wrote:

> Hi Hannes,
> 
> 
> Many thanks for the reply. With regards to your final comment I
> understand conserving mass in theory, but I am a little confused
> regarding, "keep the mass-lambdas at one end-point as they can
> interact badly with constraints". I am testing pmx on a two-molecule
> one-system I.e., G-D2K-G and G-K2D-G in the same system. How ought I
> define the mass-lambdas for this system? (nothing accurate, just an
> example would be great)?
> 
> Thanks
> Anthony
> 
> 
> On 01/06/2016 09:55,
> "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on behalf of
> Hannes Loeffler"  on behalf of hannes.loeff...@stfc.ac.uk> wrote:
> 
> >On Wed, 1 Jun 2016 07:54:56 +
> >"Nash, Anthony"  wrote:
> >
> >> In the tutorial, charges are off in the topology and the
> >> electrostatic coupling to lambda remains 0 throughout the 20
> >> windows. I assume setting col_lambdas=0 0 0 Š was for that very
> >> reason I.e., the charges were off? Could the charges not have been
> >> left on and col_lambdas defined similar to vdw_lambdas?
> >> (I understand that if charges remain constant, as vdw turns off,
> >> the system will probably blow up as attraction brings molecules
> >> infinitely close).
> >
> >Technically, Gromacs allows you to vary both vdW and Coulomb lambdas
> >simultaneously because Gromacs can apply softcore potentials to both.
> >In practice though it seems that many workers still prefer to
> >separate the two terms from each other.
> >
> > 
> >> If my transition is from a small molecule into a small molecule
> >> e.g., G-D-G to G-K-D, (the PMX paper) should I define all three
> >> lambdas: vdw_lambdas, col_lambdas and bonds_lambdas? Between
> >> states A and B, VdW, charges and bonds are all changing.
> >
> >Lambda paths are only about separating the various force field terms
> >from each other.  If you do not explicitly state any of those lambda
> >vectors they will adopt they same lambdas as specified in
> >fep-lambdas, see manual.  I do not see a reason why you would want
> >to separate out the bonded terms as well.  They are subject to a
> >linear transformation only anyway.
> >
> >What you may want to do is to keep the mass-lambdas at one end-point
> >as they can interact badly with constraints.  In a proper
> >thermodynamic cycle mass contributions must perfectly cancel.
> >
> >
> >Cheers,
> >Hannes.
> >-- 
> >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
> >
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> >https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or
> >send a mail to gmx-users-requ...@gromacs.org.
> 

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Re: [gmx-users] Clarity on TI free energy terms

[Nash, Anthony]

Hi Hannes,


Many thanks for the reply. With regards to your final comment I understand
conserving mass in theory, but I am a little confused regarding, "keep the
mass-lambdas at one end-point as they can interact badly with
constraints". I am testing pmx on a two-molecule one-system I.e., G-D2K-G
and G-K2D-G in the same system. How ought I define the mass-lambdas for
this system? (nothing accurate, just an example would be great)?

Thanks
Anthony


On 01/06/2016 09:55, "gromacs.org_gmx-users-boun...@maillist.sys.kth.se on
behalf of Hannes Loeffler"
 wrote:

>On Wed, 1 Jun 2016 07:54:56 +
>"Nash, Anthony"  wrote:
>
>> In the tutorial, charges are off in the topology and the electrostatic
>> coupling to lambda remains 0 throughout the 20 windows. I assume
>> setting col_lambdas=0 0 0 Š was for that very reason I.e., the
>> charges were off? Could the charges not have been left on and
>> col_lambdas defined similar to vdw_lambdas?
>> (I understand that if charges remain constant, as vdw turns off, the
>> system will probably blow up as attraction brings molecules infinitely
>> close).
>
>Technically, Gromacs allows you to vary both vdW and Coulomb lambdas
>simultaneously because Gromacs can apply softcore potentials to both.
>In practice though it seems that many workers still prefer to separate
>the two terms from each other.
>
> 
>> If my transition is from a small molecule into a small molecule e.g.,
>> G-D-G to G-K-D, (the PMX paper) should I define all three lambdas:
>> vdw_lambdas, col_lambdas and bonds_lambdas? Between states A and B,
>> VdW, charges and bonds are all changing.
>
>Lambda paths are only about separating the various force field terms
>from each other.  If you do not explicitly state any of those lambda
>vectors they will adopt they same lambdas as specified in fep-lambdas,
>see manual.  I do not see a reason why you would want to separate out
>the bonded terms as well.  They are subject to a linear transformation
>only anyway.
>
>What you may want to do is to keep the mass-lambdas at one end-point as
>they can interact badly with constraints.  In a proper thermodynamic
>cycle mass contributions must perfectly cancel.
>
>
>Cheers,
>Hannes.
>-- 
>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.

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Re: [gmx-users] Clarity on TI free energy terms

[Hannes Loeffler]

On Wed, 1 Jun 2016 07:54:56 +
"Nash, Anthony"  wrote:

> In the tutorial, charges are off in the topology and the electrostatic
> coupling to lambda remains 0 throughout the 20 windows. I assume
> setting col_lambdas=0 0 0 Š was for that very reason I.e., the
> charges were off? Could the charges not have been left on and
> col_lambdas defined similar to vdw_lambdas? 
> (I understand that if charges remain constant, as vdw turns off, the
> system will probably blow up as attraction brings molecules infinitely
> close).

Technically, Gromacs allows you to vary both vdW and Coulomb lambdas
simultaneously because Gromacs can apply softcore potentials to both.
In practice though it seems that many workers still prefer to separate
the two terms from each other.

 
> If my transition is from a small molecule into a small molecule e.g.,
> G-D-G to G-K-D, (the PMX paper) should I define all three lambdas:
> vdw_lambdas, col_lambdas and bonds_lambdas? Between states A and B,
> VdW, charges and bonds are all changing.

Lambda paths are only about separating the various force field terms
from each other.  If you do not explicitly state any of those lambda
vectors they will adopt they same lambdas as specified in fep-lambdas,
see manual.  I do not see a reason why you would want to separate out
the bonded terms as well.  They are subject to a linear transformation
only anyway.

What you may want to do is to keep the mass-lambdas at one end-point as
they can interact badly with constraints.  In a proper thermodynamic
cycle mass contributions must perfectly cancel.


Cheers,
Hannes.
-- 
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