Accounting for ligand conformational restriction in calculations of protein-ligand binding affinities.

ABSTRACT: The conformation adopted by a ligand on binding to a receptor may differ from its lowest-energy conformation in solution. In addition, the bound ligand is more conformationally restricted, which is associated with a configurational entropy loss. The free energy change due to these effects is often neglected or treated crudely in current models for predicting binding affinity. We present a method for estimating this contribution, based on perturbation theory using the quasi-harmonic model of Karplus and Kushick as a reference system. The consistency of the method is checked for small model systems. Subsequently we use the method, along with an estimate for the enthalpic contribution due to ligand-receptor interactions, to calculate relative binding affinities. The AMBER force field and gene

SUBMITTER: Gao C 

PROVIDER: S-EPMC2830437 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature