Hi,
>> I generate a average structures after md .
isnt that a way of undoing what you gained from doing the MD, namely a
realistic conformational ensemble? A single structure, even if it were the
global energy minimum would give you an interaction energy at best, but
you need a free energy to compare to Ki values.
>> I could'nt use MM-GBSA or PBSA due to zinc in the active site.
I believe it would be possible to incorporate Zn in MMPBSA. All you need
is a reasonable ion radius. What went wrong when you tried?
>> Is it possible to calculate a single QM/MM interaction energy for this
>> type of complex in Amber ( this was done in the paper, from which I have
>> the workflow, but they worked with the Tripos forcefield)?
You could do a QM/MM minimization of your average structure and compare
the final energies for the complexes to their Ki, but any correlation
would probably be accidental (especially if you throw away the water
around the complexes). There is an enormous amount of literature out there
on protein-ligand interactions and why it is an exceptionally hard problem
to tackle, maybe the paper you refer to is not an optimal starting point
for what you want to do...
Check out e.g.:
Michel, J. Essex, J. (2008) Hit identification and binding mode
predictions by rigorous free energy simulations. \emph{J. Med. Chem.},
\textbf{51}, 6654--6664.
Jorgensen, W. (2004) The many roles of computation in drug discovery.
\emph{Science}, \textbf{303}, 1813--1818.
Gilson, M. Zhou, H. (2007) Calculation of protein-ligand binding
affinities. \emph{Ann. Rev. Biophys. Biomol. Struct.}, \textbf{36}, 21--42.
deAzevedo, W. Dias, R. (2009) Computational methods for calculation
of ligand-binding affinity. \emph{Curr. Drug Targ.}, \textbf{9},
1031--1039.
Klebe, G. (2006) Virtual ligand screening: Strategies, perspectives and
limitations. \emph{Drug Disc. Today}, \textbf{11}, 580--594.
Gohlke, H. Klebe, G. (2002) Approaches to the description and
prediction of the binding affinity of small-molecule ligands to
macromolecular receptors. \emph{Angew. Chem., Int. Ed.}, \textbf{41},
2644--2676.
Kind Regards,
Thomas
Dr. Thomas Steinbrecher
formerly at the
BioMaps Institute
Rutgers University
610 Taylor Rd.
Piscataway, NJ 08854
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Thu Mar 10 2011 - 02:00:02 PST
