Quantum computational analysis for drug resistance of HIV-1 reverse transcriptase to nevirapine through point mutations

Quantum chemical calculation has been carried out to analyze binding interactions of nevirapine to HIV-1 reverse transcriptase (RT) and single point mutants Lys103 → Asn (K103N) and Tyr181 → Cys (Y181C). In this study, the entire system of HIV-1 RT/nevirapine complex with over 15,000 atoms is explicitly treated by using a recently developed MFCC (molecular fractionation with conjugate caps) approach. Quantum calculation of protein-drug interaction energy is performed at Hartree-Fock and DFT levels. The RT-nevirapine interaction energies are computed at fixed geometries given by the crystal structures of the HIV-1 RT/nevirapine complexes from protein data bank (PDB). The present calculation provides a quantum mechanical interaction spectrum that explicitly shows interaction energies between nevirapine and individual amino-acid fragments of RT. Detailed interactions that are responsible for drug resistance of two major RT mutations are elucidated based on computational analysis in relation to the crystal structures of binding complexes. The present result provides a qualitative molecular understanding of HIV-1 RT drug resistance to nevirapine and gives useful guidance in designing improved inhibitors with better resistance to RT mutation.