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

[Justin A. Lemkul]

Lucio Montero wrote:
> How can you test the "ligands" when you don't know if they REALLY bind 
> to the protein?
> 

Sounds like a job for docking and/or binding energy calculations.

-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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