Re: how to do: FEP e2?, a protonating mutation?

From: Sébastien Légaré (Sebastien.Legare_at_rsvs.ulaval.ca)
Date: Thu Apr 09 2009 - 10:48:06 CDT

Dear Sebastian

I am doing some pKa calculations on GLU residues from FEP. I don't know of any
script that can generate a dual topology residue for FEP from the original
residue. I had to write one by myself too (attached file) and I compared our
files. They are very similar, same charges, bonds, improper angles, IC. I do
not declare angles or dihedrals. I generate the psf with charmm and AUTOgen
generates the expected number of angles and dihedrals.

You have some bonds that are declared twice. It might depend on how you
generate your system from your E2B topology, but I know that this will cause
problems with charmm (on version 33 at least).

I would also like to talk about one particular problem with carboxylic acids
in FEP. Because of the high energy barrier between syn and anti conformations
of the carboxyl hydrogen, the protonated state gets stuck in the unfavorable,
anti conformation, if the dummy hydrogen went to anti while unprotonated.
This have a strong effect on the computed free energy. Some workarounds were
proposed. The one I prefer is to raise the barrier to 6.0 kcal/mol and start
in syn conformation to ensure that this conformation is conserved even in the
unprotonated state as proposed by J. Khandogin (Biophys. J. 2005, 89,
141-157), see "Protonation state models" section.

Is it safe to say that raising this barrier does not affect the computed free
energy otherwise than by ensuring a syn conformation?

Regards

Sébastien

On April 7, 2009 08:15:19 pm Sebastian Stolzenberg wrote:
> Dear All,
>
> I am trying to write my own FEP mutation: GLU -> GLUP.
>
> Attached you will find my first attempt (the "B" in "E2B" I defined for
> "GLUP"). Is the logic for this right? (I don't expect you guys to look
> for typos).
>
> Is there a nice script doing these things in a breeze?
>
> Cheers,
> Sebastian

-- 
Sébastien Légaré
Ph. D. Student
Laval University
Quebec, Canada, G1V 0A6
418-656-2131 #11577

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