Implication of Natural Polymorphism in Hinge Region of HIV-1 Protease on Protein Conformations, Local Structures and Backbone Dynamics

Abstract

HIV-1 protease (PR) serves as an important drug target because its inhibition generates immature non-infectious virions. However, drug-pressure selected mutations, along with natural polymorphisms, can lead to drug resistance to HIV-1 protease inhibitors (PIs), which change the drug binding configuration and equilibrium protease conformational sampling. As was suggested in our previous study, (1) a new protease conformation, curled-open, was identified in constructs carrying natural polymorphisms including E35D, and consequently, these constructs displayed higher protein backbone dynamics compared with wild-type subtype B construct characterized by nuclear magnetic resonance (NMR) spectroscopy. In the present work, we discuss the impact of the single E35D natural polymorphism on generating a minor protease conformation (curled-open), and consequently, influencing the protein structure and dynamics. The combined results from Double electron-electron resonance (DEER), NMR spectroscopy and X-ray crystallography structures provide a possible structural mechanism for altered conformational dynamics.