Ab initio calculation of the interaction energy in the P2 binding pocket of HIV-1 protease

Interactions at the P2 binding pocket of human immunodeficiency virus type 1 (HIV-1) protease have been studied using calculated interaction energies for model systems that mimic this binding pocket. Models were built for the P2 pocket of HIV-1 protease in complex with TMC114, nelfinavir, and amprenavir. A two-step procedure was applied. In the first step, the size of the model system was confined to similar to 40 atoms, and the interaction energy was calculated at different computational levels. In the second step, the size of the system was increased to 138 atoms, and the calculations were only performed at the HF/6-31G** level. The interaction energy of the HIV-1 protease/TMC114 complex was found to be more favorable than the interaction energies of the other complexes because of the additional hydrogen bond interaction this inhibitor is able to make with the HIV-1 protease backbone. The results of the calculations are supported by stockholder charges and electrostatic potential maps. (c) 2005 Wiley Periodicals, Inc.