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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