On Fri, Jun 19, 2015 at 5:29 AM, Marc van der Kamp <marcvanderkamp.gmail.com
> wrote:
> Dear all,
>
> I have noticed (in a few different projects/proteins) that when Asp or Glu
> are treated as protonated (ASH/GLH), the hydrogen on OD2/OE2 can change to
> a 'cis' position, i.e. the CB-CG-OD2-HD2 dihedral is ~0 degrees, as opposed
> to the normal 'trans' position (with a CB-CG-OD2-HD2 dihedral of ~180
> degrees).
> The .lib files of course define the hydrogen position to be in the normal
> 'trans' position, so the change to 'cis' happens during simulation.
> This occurs with ff14SB for example (but also with the related force
> fields, and quite possibly more), and usually when there is a good hydrogen
> bond acceptor nearby. It then usually stays in this conformation for the
> remainder of the simulation.
>
> Have others noticed this?
> Perhaps those that work with constant pH MD?
>
> I am always somewhat suspicious when seeing such a cis conformation, as it
> is not one I would expect to be very stable compared to the 'normal' trans
> conformation (on QM grounds).
> I must admit I haven't looked into this issue in any detail - perhaps
> others have?
> I would be grateful for any experience people have or know about (e.g.
> references) regarding this issue.
>
It's not particularly unusual for both positions to be populated during
the course of a simulation. The energy difference is not so large as to
preclude cis- conformers from being sampled. It may be that the cis-
conformer is stabilized by some hydrogen bonds somewhere (worth checking).
It may also be that the cis-conformer is being kinetically trapped, since
there is a fairly sizeable barrier between cis- and trans- interconversion.
(I ran the calculation at some point, I simply don't remember what it is).
This is actually one of the strengths of constant pH MD and the choice of
putting 4 hydrogens (one in each of the cis- and trans- positions on both
oxygens) on carboxylate functional groups. The cis-trans populations are
sampled by MC directly without having to pass over the barrier, meaning
that those distributions are sampled far more quickly. So an option is
always to use CpHMD (or pH-REMD if you have access to it) to see if you get
the same cis- and trans- distributions with CpHMD as you do with regular
MD. For simple test systems (e.g., an isolated ASP or GLU residue), I get
the same distributions in CpHMD at low pH (to make sure I don't sample the
deprotonated state) as I do in a regular MD simulation. That might help
you decide whether you have a sampling problem or some atypical carboxylate
residues.
HTH,
Jason
--
Jason M. Swails
BioMaPS,
Rutgers University
Postdoctoral Researcher
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Received on Fri Jun 19 2015 - 09:30:03 PDT
