An integrated molecular dynamics, principal component analysis and residue interaction network approach reveals the impact of M184V mutation on HIV reverse transcriptase resistance to lamivudine

Abstract

The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development. Amongst those mutations, M184V was found to cause a complete loss of ligand fitness. In this study, we report the first account of the molecular impact of M184V mutation on HIV RT resistance to 3TC (lamivudine) using an integrated computational approach. This involved molecular dynamics simulation, binding free energy analysis, principle component analysis (PCA) and residue interaction networks (RINs). Results clearly confirmed that M184V mutation leads to steric conflict between 3TC and the beta branched side chain of valine, decreases the ligand (3TC) binding affinity by ∼7 kcal mol(-1) when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network. The comprehensive molecular insight gained from this study should be of great importance in understanding drug resistance against HIV RT as well as assisting in the design of novel reverse transcriptase inhibitors with high ligand efficacy on resistant strains.

Insights on the structural perturbations in human MTHFR Ala222Val mutant by protein modeling and molecular dynamics

“…After the docking of the wild-type MTHFR-FAD complex, the Alanine 222 residue was mutated to valine using the graphical user interface (GUI) of Chimera (Pettersen et al, 2004), in order to generate the mutated variant. Both the wild and mutated (Ala222Val) MTHFR-FAD complexes were subjected to an all-atom molecular dynamics simulation using the previously reported parameters provided by Bhakat, Martin, and Soliman (2014) and Karubiu, Bhakat, and Soliman (2014). During molecular dynamics simulation, the effect of in silico mutations was monitored by performing different postdynamics analyses as described by Bhakat et al (2014).…”

Mechanism of Inhibition of Hsp90 Dimerization by Gyrase B Inhibitor Coumermycin A1 (C–A1) Revealed by Molecular Dynamics Simulations and Thermodynamic Calculations

“…Principle component analysis (PCA) is extensively used to effortlessly examine and identify data generated from MD simulations to highpoint principal modes accountable for changes in conformation [11]. The PTRAJ and CPPTRAJ modules were used in performing PCA C-alpha atoms [48] integrated with Amber 14 [13] The plots analysis showing the central conformational motions descriptive of each structure were created using Origin data analyses programme (www.originlab.com).…”

“…It has also been reported that the nucleotide binding site situated at the CTD is more favorable to guanosine-5 0 -triphosphate (GTP) over ATP, which would possibly enhance the selectivity of the new inhibitors against this site [9,17,59]. Herein we focus on the C-terminal dimerization inhibitors as this is the vital domain for the biological activity of Hsp90 [11].…”

“…The heightened utilities of the PD methods demonstrated to be effectual in comprehending the conformational background of biological macromolecules. The most extensively improved PD methodologies used to seek structural variations within distinctive biological phenomenas include principal component analysis PCA or essential dynamics (ED) [11]. Although PCA has attested its competency to be implement in the likening of motions of different macromolecules there are additional techniques, which were applied to understand such biological conformational behaviors [9,49].…”

“…Highly active antiretroviral therapy (HAART), approved by the Food and Drug Administration (FDA), is currently the most effective therapeutic regimen decreasing the viral load, which prolongs the survival of AID-free patients [4,40,58]. These drugs include inhibitors of three essential HIV enzymes protease, integrase (IN), reverse transcriptase (RT) as well as entry and progression enzyme inhibitors of in the HIV life cycle [11,41]. In spite of all currently existing anti-HIV therapies, resistant strains still poses a problem.…”