Unfavorable anti conformation after GLUP patching?

From: Sebastian Stolzenberg (s.stolzenberg_at_gmail.com)
Date: Tue Apr 14 2009 - 19:13:21 CDT

Salut Sébastien,

thank you very much for your helpful comments.
> 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.
so for GLUP, the syn/anti conformations are defined through the dihedral
HE2-OE2-CD-CG, (syn=0-90degs,anti=90-180degs), right?

If yes, I see my protonated GLUP side chain in my FEP-residue E2EP
(=E2B) in the unfavorable anti conformation (=180degs.), right after
running VMD psfgen.

Your concern is also important for doing simple GLUP patches in a plain
MD run, right? I did some tests, and found that the GLUP patch leaves
the HE2-OE2-CD-CG dihedral in the unfavorable anti-conformation. I bet
even long equilibration runs will not fix this issue!

I this concern you mentioned noted somewhere in the topology documentations?

Thanks again,
> 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

This archive was generated by hypermail 2.1.6 : Wed Feb 29 2012 - 15:52:36 CST