EMPIRICAL FREE-ENERGY CALCULATIONS OF LIGAND-PROTEIN CRYSTALLOGRAPHICCOMPLEXES .1. KNOWLEDGE-BASED LIGAND-PROTEIN INTERACTION POTENTIALS APPLIED TO THE PREDICTION OF HUMAN-IMMUNODEFICIENCY-VIRUS-1 PROTEASE BINDING-AFFINITY

The steadily increasing number of high-resolution human immunodeficien cy virus (HIV) 1 protease complexes has been the impetus for the elabo ration of knowledge-based mean field ligand-protein interaction potent ials. These potentials have been linked with the hydrophobicity and co nformational entropy scales developed originally to explain protein fo lding and stability, Empirical free energy calculations of a diverse s et of HIV-1 protease crystallographic complexes have enabled a detaile d analysis of binding thermodynamics, The thermodynamic consequences o f conformational changes that HIV-1 protease undergoes upon binding to all inhibitors, and a substantial concomitant loss of conformational entropy by the part of HIV-1 protease that forms the ligand-protein in terface, have been examined. The quantitative breakdown of the entropy -driven changes occurring during ligand-protein association, such as t he hydrophobic contribution, the conformational entropy term and the e ntropy loss due to a reduction of rotational and translational degrees of freedom, of a system composed of ligand, protein and crystallograp hic water molecules at the ligand-protein interface has been carried o ut. The proposed approach provides reasonable estimates of distinction s in binding affinity and gives an insight into the nature of enthalpy -entropy compensation factors detected in the binding process.