Improved Binding Free Energy Predictions from Single-Reference Thermodynamic Integration Augmented with Hamiltonian Replica Exchange.

ABSTRACT: Reliable predictions of relative binding free energies are essential in drug discovery, where chemists modify promising compounds with the aim of increasing binding affinity. Conventional Thermodynamic Integration (TI) approaches can estimate corresponding changes in binding free energies, but suffer from inadequate sampling due to ruggedness of the molecular energy surfaces. Here, we present an improved TI strategy for computing relative binding free energies of congeneric ligands. This strategy employs a specific, unphysical single-reference (SR) state and Hamiltonian replica exchange (HREX) to locally enhance sampling. We then apply this strategy to compute relative binding free energies of twelve ligands in the L99A mutant of T4 Lysozyme. Besides the ligands, our approach enhances hind

SUBMITTER: Khavrutskii IV 

PROVIDER: S-EPMC3200539 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature