[gmx-users] HF/6-31G** ESP derived charges to replace PRODRG assigned ones

[Josmar R. da Rocha]

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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