AMBER Archive (2006)

Subject: Re: AMBER: RMSD: is it related to flexibility?

From: a a (patd_2_at_hotmail.com)
Date: Wed Oct 04 2006 - 23:15:20 CDT

Dear David,

Thank you very much for your comments. The following is the experimental
work done previously. Both the wild type and mutated proteins form a
covalent complex with a drug. They both modified the drug to a metabolite.
  Experimentally, we measured the metabolite concentration over the time,
and found mutant one produce metabolite ten times faster than the wild type.
  We originally expected that it is due to different binding affinity of the
drug, but finally we found the binding affinities for these two proteins to
the drug are the same both experimentally and theoretically (docking). As
it is well documented that the rate for these protein to release the
metabolite is a function of a flexibility of a loop on these proteins (the
loop is mutated). Thus, we try to see if the mutation change the
flexibility of the loop theoretically, so as to explain the increased rate.

Follow the tutorial on the web, I carried out minimization, equilibrium and
a production 1-ns MD with sander for these two proteins, and double checked
that the potential energies are stable at the production period. This is
the preliminary result that we got. The RMSD (reference to a PDB file) of
the loop of the wild type protein in average is 2.0, but 3.0 for the mutant
one. The RMSD vs time plot shown that the RMSD increase from zero and
reach stable (~ 4 A) at ~300 ps for the wild type and ~200 ps for the
mutant. Is the difference in terms of RMSD (1-2 A) and time to reach stable
(100 ps) significant enough for drawing any conclusions?

If not, could you mind to suggest the best way to model the release rate of
metabolite B from these two proteins?

I am new to MD calculations, just learn it several months ago from the
websites, your professional suggestions are valuable to me. Many thanks in
advanced.

Best regards,

Ann

>From: "David A. Case" <case_at_scripps.edu>
>Reply-To: amber_at_scripps.edu
>To: amber_at_scripps.edu
>Subject: Re: AMBER: RMSD: is it related to flexibility?
>Date: Wed, 4 Oct 2006 08:08:32 -0700
>
>On Wed, Oct 04, 2006, a a wrote:
> >
> > I got two protein structures with different performance on the loop
> > mobilitiy, one of them move very fast, another one is about 10 time less
> > flexible, based on our experimental data.
>
>The answer probably depends on what kind of experimental data one is
>talking
>about here; that will effectively determine what is being measured and
>represented as "flexibility". And that, in turn, will help decide what
>sorts
>of calculations might be relevant.
>
>...regards...dac
>
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