On 16 September 2014 19:13, Jason Swails <jason.swails.gmail.com> wrote:
> On Tue, 2014-09-16 at 17:05 +0300, Thomas Evangelidis wrote:
> > Greetings,
> >
> > I want to run MMPBSA.py script using 3 different trajectories (complex,
> > receptor, ligand). The difference between the receptor and the complex
> > trajectories was that the receptor had an aspartate protonated which was
> > unprotonated in the complex. This is perfectly fine in reality, but when
> it
> > attempted to use MMPBSA.py the program complained.
>
> This is actually not fine (at least not according to the details you've
> written here). The MM/PBSA thermodynamic cycle does not accommodate
> "chemical" changes (i.e., changes in covalent bonds). There is an extra
> process of deprotonation and proton desolvation that is not accounted
> for. So you would need to add on a thermodynamic cycle similar to the
> kind used for pKa calculations and constant pH simulations.
>
> > So I modified the
> > receptor trajectory and topology by removing the extra proton from the
> ASP
> > side-chain. However, I still get a residue mismatch error that may be
> cause
> > by the modification I introduced. Do you believe this is the case? If
> yes,
> > is there any work around to fix it?
>
> MMPBSA.py takes steps to catch errors that break the assumptions of
> MM/PBSA analyses (like what you are doing here). [1] Simply stripping
> the extra proton will not work -- MMPBSA.py also checks that the residue
> sequences are the same in the bound and unbound states (ASH != ASP) and
> it checks that the atoms have the same charges in the bound and unbound
> states... which they won't if all you did was strip out a hydrogen atom
> using cpptraj.
>
> You can use MMPBSA.py to process each trajectory independently and then
> combine them yourself as legs of the applicable thermodynamic cycle for
> your process.
>
>
>
Good point. The protein is a transporter with a binding pocket that becomes
solvent exposed (outward facing conformation) when ASP51 is protonated
(ASH51). So the receptor trajectory was actually created to monitor the
opening of the substrate binding cavity. Deprotonation of ASH51 occurs upon
ligand binding and triggers the occluded ==> inward facing transition. My
purpose is to compare free energies of binding for a series of analogues
with know kinetics. This protonation-deptonation is associated with large
conformational changes and hence a significant entropic change which is
impossible to estimate. So I thing my best bet is to calculate relative
free energies between the ligands (given that the entropic cost of binding
is quite similar for each of them) by using only the complex trajectories I
have.
I tried to do that for one complex but I am getting a series of errors of
the following type:
PB Bomb in pb_aaradi(): No radius assigned for atom 65 CB 3C
PB Bomb in pb_aaradi(): No radius assigned for atom 79 CB 2C
PB Bomb in pb_aaradi(): No radius assigned for atom 115 CG CO
These are associated with protein atoms, which is strange since I used
ff14sb. I tried to correct them with parmed.py using:
change AMBER_ATOM_TYPE .%CB C
change AMBER_ATOM_TYPE .%CG C
Is this correct? Should all these carbons be of type 'C' ?
thanks,
Thomas
--
======================================================================
Thomas Evangelidis
PhD student
University of Athens
Faculty of Pharmacy
Department of Pharmaceutical Chemistry
Panepistimioupoli-Zografou
157 71 Athens
GREECE
email: tevang.pharm.uoa.gr
tevang3.gmail.com
website: https://sites.google.com/site/thomasevangelidishomepage/
===============================================================
*Physics is the only real science. The rest are just stamp collecting.*
*- Ernest Rutherford*
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Received on Wed Sep 17 2014 - 09:00:02 PDT
