Well, based on your responses I would have two main comments:
1) I would HIGHLY recommend using RED/RESP server to get those charges and
make a proper input .lib for LeAP. Taking parameters from Tyr, will
certainly give you something close, but the Guassian methods employed by
RESP will allow for accurate partial charge distribution as a result of the
two rings being nearby, which is likely to have a LARGE effect on some of
those atoms. I understand you're just experimenting at this point, but
using the server is actually not so complicated in the case where you just
have a single zero net charge molecule that doesn't need to be attached to
anything.
2) You say the cis-form becomes dominant upon aging or UV. So what this
tells me is that the trans-form of the molecule is more stable as your MD
suggests, and it is some kind of modification to the molecule (likely
oxidation) that changes the structure and makes the cis-form of this
modified molecule more stable. So, if this aging thing is what you are
interested in, I'd think you'll need to determine the molecular structure
of the aged stuff (probably via NMR/mass spec or small molecule
crystallography) and then use that in RESP, and only then would I expect
you'd see the cis-form dominate.
~Aron
On Thu, Oct 18, 2012 at 2:10 PM, bio lab <biolabcs.gmail.com> wrote:
> First of all, thanks for your comments.
>
> > You can use methods such as umbrella sampling [..] or metadynamics [..]
> > (rather than relying on chance observations during your equilibrium MD
> run).
>
> Agreed. But I have never used those techniques myself and I am afraid of
> ending up multiplying my problems rather than solving one of them. :) I
> think maybe I could first experiment a bit with energy minimization
> starting from a configuration close (but not equal) to cis. So far, I only
> tried to experiment with high-temperature MD to encourage the transition.
>
> > If the cis-form is really more stable
>
> As a matter of fact, the trans isomer is the natural form, but
> experimentally in aqueous solution it converts to (and remains) cis upon
> aging of the sample, or by sunlight radiation.
>
> > I don't know if GAFF or AMBER are particularly well setup to handle
> accounting
> > for the effects of pi-electrons (maybe someone can comment). [..]
> > there may also be significant polarization effects that you aren't
> > taking into account unless you use a polarizable forcefield.
>
> I really hope that someone can comment on that, too. After all, this looks
> to me a basic question of molecular modeling (such as "can classical MD
> model this kind of system?").
>
> > Having said all that, maybe it can still work but you just haven't
> derived
> > the charges accurately. How did you get the partial charges, did you use
> > the RESP server?
>
> Indeed, optimization of charges was intended to be my following step. In
> fact, at the moment I am using charges suggested by UCSF Chimera (AM1-BCC),
> as they looked reasonable compared to those used in Amber99SB, e.g. in the
> side-chain of a TYR residue. The next step should have been to use the RED
> server, but any other suggestion is welcome.
>
> Still, I have the sensation that this issue could affect the detailed
> optimization of the final structure, but not prevent altogether the
> possibility of reaching a cis (or quasi-cis) conformation.
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>
--
Aron Broom M.Sc
PhD Student
Department of Chemistry
University of Waterloo
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Received on Thu Oct 18 2012 - 13:00:03 PDT
