How can you test the "ligands" when you don't know if they REALLY bind to
the protein?
--------------------------------------------------
From: "Ran Friedman, Biochemisches Inst." <r.fried...@bioc.uzh.ch>
Sent: Friday, March 27, 2009 2:35 PM
To: <bije...@yahoo.com.br>; "Discussion list for GROMACS users"
<gmx-users@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...@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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