title: Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations.
abstract: HIV-1 reverse transcriptase (RT) is a multifunctional enzyme that is targeted by nucleoside analogs (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NNRTIs are allosteric inhibitors of RT, and constitute an integral part of several highly active antiretroviral therapy regimens. Under selective pressure, HIV-1 acquires resistance against NNRTIs primarily by selecting mutations around the NNRTI pocket. Complete RT sequencing of clinical isolates revealed that spatially distal mutations arising in connection and the RNase H domain also confer NNRTI resistance and contribute to NRTI resistance. However, the precise structural mechanism by which the connection domain mutations confer NNRTI resistance is poorly understood. We performed 50-ns molecular dynamics (MD) simulations, followed by essential dynamics, free-energy landscape analyses, and network analyses of RT-DNA, RT-DNA-nevirapine (NVP), and N348I/T369I mutant RT-DNA-NVP complexes. MD simulation studies revealed altered global motions and restricted conformational landscape of RT upon NVP binding. Analysis of protein structure network parameters demonstrated a dissortative hub pattern in the RT-DNA complex and an assortative hub pattern in the RT-DNA-NVP complex suggesting enhanced rigidity of RT upon NVP binding. The connection subdomain mutations N348I/T369I did not induce any significant structural change; rather, these mutations modulate the conformational dynamics and alter the long-range allosteric communication network between the connection subdomain and NNRTI pocket. Insights from the present study provide a structural basis for the biochemical and clinical findings on drug resistance caused by the connection and RNase H mutations.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, 08854; Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, 08854.
authors.forename: R S K
authors.initials: RS
authors.lastname: Vijayan
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
authors.forename: Kalyan
authors.initials: K
authors.lastname: Das
mesh_terms: D055162:Biocatalysis; D020134:Catalytic Domain; D004279:DNA, Viral; D024882:Drug Resistance, Viral / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D019829:Nevirapine / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: N348I; RNase H; T369I; allosteric communication; connection mutations; drug resistance; protein structural network