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
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