AMBER Archive (2007)

Subject: AMBER: testing protein stability

From: Sally Pias (sallypias_at_gmail.com)
Date: Fri Jun 22 2007 - 00:24:58 CDT

I would like to use AMBER to test the stability of a protein following
mutation. The three-dimensional structure of the wild-type protein is
known, and I have introduced in silico mutations using DeepView (Swiss
PDB Viewer). However, I am not sure if testing stability with MD
simulations is a reasonable goal. If so, what kind of protocol would
one use?

I had planned to heat up the wild-type and mutant proteins in separate
MD simulations, in order to identify a temperature threshold for the
stability of each. By comparing the thresholds, I could get a measure
of the relative stability of the mutant vs. the wild-type protein.

I have already conducted a 5 ns production run for the mutant and
found that it was stable on that timescale at 300 K, with explicit
solvent. Still, the question is whether the mutant polypeptide would
actually fold into the same three-dimensional structure as the
wild-type and, if so, whether its dynamics and stability would be
similar to those of the wild-type structure. I think the protein is
probably too large (185 residues) for running a folding simulation.
Thus, I am trying to test whether the mutant would be stable if it did
take on the exact fold of the wild-type protein. (The mutations
disrupt a zinc ion binding site that is likely to be involved in
stabilizing the structure.)

Any guidance would be appreciated.

Thanks,
Sally Pias
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