Regards,
Josmar Rocha
--- Em *sex, 27/3/09, Ran Friedman, Biochemisches Inst.
/<r.fried...@bioc.uzh.ch>/* escreveu:
De: Ran Friedman, Biochemisches Inst. <r.fried...@bioc.uzh.ch>
Assunto: Re: [gmx-users] HF/6-31G** ESP derived charges to replace
PRODRG assigned ones
Para: bije...@yahoo.com.br, "Discussion list for GROMACS users"
<gmx-users@gromacs.org>
Data: Sexta-feira, 27 de Março de 2009, 17:35
Dear Josmar,
You haven't written which force field you plan to use. For OPLS and
AMBER
QM-based optimisation should be fine. In Gromos, the FF was developed
with the
aim of reproducing experimental results and I'm not sure if you can
find a
better solution than examining other residues with the same chemical
moieties or
use the same approach as reported in the relevant manuscripts. Some
software
packages can also be used - these are mostly proprietary and not so
easy to use.
Once you derive the parameters, it's a good idea to make some test
runs of
the ligands and see if they behave as expected before you actually run
a
simulation with the
protein. For example, if a conjugate ring system isn't
planar something may be wrong in the setting.
There's no easy solution - this is why it's considered an advanced
topic. It is, however, very important. I've encountered a ligand that
leaves
its binding site during a simulation due to wrong parameters (in this
case, the
protonation of a protein side chain - FEBS 581, Pages 4120-4124,
2007).
Hope that helped,
Ran
On Fri, 27 Mar 2009 12:22:01 -0700 (PDT)
"Josmar R. da Rocha" <bije...@yahoo.com.br> wrote:
> Dear users,
>
> I have been reading some posts about using externally computed
charges to
replace Prodrg charges at ligand topology files. Many users commented
on the low
trustability given to Prodrg charges (e.g
http://www.mail-archive.com/gmx-users@gromacs.org/msg02360.html ;
http://www.mail-archive.com/gmx-users@gromacs.org/msg17351.html ). Dr.
Verli
pointed out the
use of semi-empirical methods such as RM1 in cases not involving
simulations with sulphate or phosphate groups (what is not my case)
and the use
of QM methods with the 6-31G** basis set, for example, to obtain
robust charges
(http://www.mail-archive.com/gmx-users@gromacs.org/msg03410.html). On
the other
hand Dr. Mobley defined as a "a bad idea to compute charges for an
all-atom
case using QM and then try to convert these to a united atom force
field".
Other users advice that the best charges are that compatible with the
force
field parametrization
> (http://www.mail-archive.com/gmx-users@gromacs.org/msg10760.html ;
http://www.mail-archive.com/gmx-users@gromacs.org/msg08308.html),
usually
pointing to http://wiki.gromacs.org/index.php/Parameterization. Dr
Friedman
suggested that "to calculate the electrostatic potential over the
whole
molecule, and fit the atomic charges so that they reproduce this
potential"
in
order to make it less sensitive to small changes in the geometry of
the
molecule may give good results
(http://www.mail-archive.com/gmx-users@gromacs.org/msg08308.html). Dr.
Lemkul
stressed the need for charges refinement to reproduce
experimentally-observed
behavior while trying to use QM charges with Gromos ff. since
"Parameterization under Gromos usually involves empirical derivation
of
physical parameters, and free energy calculations using thermodynamic
integration". Few examples of protein-ligand studies using Gromacs and
Gromos96 ff that I have access (from literature) seem to treat it as
"take
it for granted" issue (any reference with a more detailed description
would
be welcome :-)). Despite reading on this topic I could not compile all
the
information in a clear and objective way (may be because I'm in the
wrong
track). Let ask you some question that I find would help me to make my
ideas
more
clear:
>
>
> 1-am I overestimating the importance of ligand charges in such a
simple
study of protein-small molecule (containg charged Phosphate groups)
complex? or
>
> 1.1-The only way to test for this is doing many different simulation
on
the same system using different type of computed charges to see what
happen?
>
> 2-How could I try to choose a method to obtain reasonable charges
based on
the reproduction of experimentally-observed behavior if I do not have
experimental data for my system?
>
> 3-I also would like to know from users dealing with protein-ligand
interactions studies what do you consider a good approach to address
this
problem?
>
> Based on what I read I'd have a tendency to use HF/6-31G** ESP
derived
charges (with necessary changes as to make it united-atom charges and
scaling
that to a integer number for each group). Please, let me know if
that strategy
would be as good as a disaster!
> Thank you very much for the attention.
>
>
> Josmar Rocha
>
>
>
> Veja quais são os assuntos do momento no Yahoo! +Buscados
> http://br.maisbuscados.yahoo.com
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