Calculation of binding affinities of HIV-1 RT and β-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches

Abstract

The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets of HIV-1 RT and beta-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), 'shell' and periodic boundary condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect to experimental binding free energy estimates for both systems: for instance, 'PB' fits on MD trajectories carried out with PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol(-1) and coefficients of determination, r (2) of 0.76 and 0.75 for the HIV-1 RT and beta-Secretase sets. However, it was also found that results from MD sampling using PBC solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization sampling.