We will discuss the use of explicit solvent molecular dynamics based free energy perturbation (FEP) methods to calculate protein-ligand binding affinities. Improvements in sampling methods and the molecular mechanics force fields have enabled the development of a robust methodology that consistently delivers root mean square errors less than 1 kcal/mole. FEP methods can be applied to determine changes in protein-protein interactions upon mutation as well as the binding of small molecule ligands to receptors.  A key motivation for the use of FEP is the ability to elucidate the effects of conformational flexibiity of the receptor, which is very difficult to accomplish with simpler, empirically based approaches. Extensive comparison with experimental data will be presented for a wide variety of systems.

Calculation of protein-ligand binding affinities via free energy perturbation methods

251st National Meeting (2016)

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