title: Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations.
abstract: Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Suri
authors.initials: S
authors.lastname: Moonsamy
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.|Division of Biophysical Chemistry, Lund University, P.O. Box 124, SE-22100, Lund, Sweden.
authors.forename: Soumendranath
authors.initials: S
authors.lastname: Bhakat
authors.affiliation: San Diego Supercomputer Center & Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, CA, 92093-0505, USA.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Walker
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa. soliman@ukzn.ac.za.
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D019259:Lamivudine / Q000737:chemistry / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D054303:HIV Reverse Transcriptase
keywords: Binding free energy calculations; HIV-RT; Lamivudine resistance; M184I mutation; Multiple molecular dynamic simulations