Hi,
I believe with such charge mutations there are two possible sources of error:
a) Is the model applicable, i.e. is it ok to simulate a transition in
which the total system charge changes with Amber's TI routines. In my
personal opinion, we can answer that with a yes, even if problems may
exist in special cases. Others on the list will most likely have their own
ideas and caveats to add. We got good results for the free energy of
solvation for charged compounds in many cases, but of course the question
what the 'right' answer is here is an interesting one by itself.
b) is the simulation good enough, i.e. does a typical MD simulation
capture the full system response for an electrostatic change? That is much
more system dependent and in case of proteins, far from certain (Apart
from conformational changes, think about things like protonation state
changes or bound ions). van der Waals changes and directed interactions
are much more local in the force field picture than electrostatics, so a
mutation changing such interactions may converge a lot quicker than one
involving charges.
Without further knowledge of your calculations, I cant say for sure, but I
wouldnt be suprised if your bad results were caused by type b) problems
more than type a)
> We have tried to mutate a +2 ligand to +1 ligand and got much worse
> results, compared to when we mutated a +2 to +2 ligand. We have not
> gone further with this investigation, and we do not know if we can
> trust the results. Let me know if you get good results.
Kind Regards,
Thomas
Dr. Thomas Steinbrecher
BioMaps Institute
Rutgers University
610 Taylor Rd.
Piscataway, NJ 08854
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Received on Wed Jan 27 2010 - 07:00:04 PST
