Subject: free energy calc

From: Christophe L M J Verlinde <[email-masked]>
Date: Thu, 25 Jul 2002 10:28:40 -0700 (PDT)

Dear CCLers,

We have been trying to "predict" the free energy change
for replacing a neutral inhibitor bound to a protein
into an isosteric one with a -1 charge via a 
thermodynamic cycle. Our approach consists of MD
simulations with and explicit waters (TIP3P). We have
tried both FEP and TI. We also experimented with 
particle mesh Ewald techniques. The bottom line is
that the calculations are off by 2.5 to 5 kcal/mol
> from reality depending on the protocol (we used
the AMBER6 package). The problem probably does
not reside in proper sampling as the simulations
reproduce the conformational change seen between
the 2 complexes (we have high resolution X-ray structures).

Has anyone had any success with such type of simulations,
i.e. cases involving a net change in charge? If so,
could you provide us with recommended protocols.

Thanks

Christophe L.M.J. Verlinde

Biomolecular Structure Center
University of Washington - Box 357742
Seattle, WA 98195
T:(206)543-8865 F:(206)685-7002
URL: www.bmsc.washington.edu/people/verlinde