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

[Lucio Montero]

How can you test the "ligands" when you don't know if they REALLY bind to 
the protein?

--------------------------------------------------
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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