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

[Justin A. Lemkul]

Lucio Montero wrote:
> How about MOPAC to calculate the charges for 3-methyladenine (this 
> molecule has a charge +1) for using the G43a1 force field?.
> 
> 

That may not be a bad place to start, but any parameters applied to a Gromos 
molecule have to reproduce condensed phase thermodynamic observables.  Empirical 
fitting of the initial parameters may be required.  Refer to the primary 
literature.  The reference for the 53a5 and 53a6 parameter sets are published in 
JCC, which may provide you with some useful information.

-Justin

> --------------------------------------------------
> From: "Ran Friedman, Biochemisches Inst." <r.friedman at bioc.uzh.ch>
> Sent: Friday, March 27, 2009 2:35 PM
> To: <bije_br at yahoo.com.br>; "Discussion list for GROMACS users" 
> <gmx-users at gromacs.org>
> Subject: Re: [gmx-users] HF/6-31G** ESP derived charges to replace    
> PRODRGassignedones
> 
>> 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_br at 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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-- 
========================================

Justin A. Lemkul
Graduate Research Assistant
ICTAS Doctoral Scholar
Department of Biochemistry
Virginia Tech
Blacksburg, VA
jalemkul[at]vt.edu | (540) 231-9080
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin

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