HIV-1 Proteinase Inhibitor Binding. The Effect of Active Site Conformational Restraints on Calculated free Energies of Ligand Binding

Abstract

In this article, results are presented for the calculation of the free energy difference between the S and R stereomeric form of the Human Immunodeficiency Virus I proteinase (HIV-PR) inhibitor Val-Ser-Gln-Asn-Ler-Vac-Ile-Val, where Ler-Vac represents the dipeptide Leu ψ [CHOH-CH2]Val, in which the peptide bond has been replaced by the hydroxy-ethylene moiety. The difference in free energy of binding of the two diastereomers was evaluated, using restraint potentials to keep the active site aspartyl diad in a planar conformation. The S-conformation is found to bind stronger to the HIV-PR than the R stereomer by 31.7±0.5 kJ mol-1. However the restraints are found to be of different strengths in the two stereomers. Relaxation of the restraints lowers the free energy of the S-stereomer by 24.6±1.1 kJ mol-1, and the R-stereomer by 34.4±1.9 kJ mol-1. The difference in free energy of binding of the two stereomers is, therefore, only 21.9 kJ mol-1 when the active site diad is not restrained to a planar conformation.