ArticleThe journal of physical chemistry. B2012
Interaction of I50V mutant and I50L/A71V double mutant HIV-protease with inhibitor TMC114 (darunavir): molecular dynamics simulation and binding free energy studies.
Article in The journal of physical chemistry. B, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 75 citations in OpenAlex.
- Article
- An Updated Review on Developing Small Molecule Kinase Inhibitors Using Computer-Aided Drug Design Approaches.International journal of molecular sciences · 2023Review
- Dynamozones are the most obvious sign of the evolution of conformational dynamics in HIV-1 protease.Scientific reports · 2023Article
- Evolving Mutational Buildup in HIV-1 Protease Shifts Conformational Dynamics to Gain Drug Resistance.Journal of chemical information and modeling · 2023Article
- Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants.International journal of molecular sciences · 2022Article
- Targeting the DENV NS2B-NS3 protease with active antiviral phytocompounds: structure-based virtual screening, molecular docking and molecular dynamics simulation studies.Journal of molecular modeling · 2022Article
- Multiple Molecular Dynamics Simulations and Energy Analysis Unravel the Dynamic Properties and Binding Mechanism of Mutants HIV-1 Protease with DRV and CA-p2.Microbiology spectrum · 2022Article
- Systematic analysis and molecular profiling of EGFR allosteric inhibitor cross-reactivity across the proto-oncogenic ErbB family kinases by integrating dynamics simulation, energetics calculation and biochemical assay.European biophysics journal : EBJ · 2022Article
- The structural, dynamic, and thermodynamic basis of darunavir resistance of a heavily mutated HIV-1 protease using molecular dynamics simulation.Frontiers in molecular biosciences · 2022Article
- Structural Impacts of Drug-Resistance Mutations Appearing in HIV-2 Protease.Molecules (Basel, Switzerland) · 2021Article
- Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors.Retrovirology · 2020Article
- Picomolar to Micromolar: Elucidating the Role of Distal Mutations in HIV-1 Protease in Conferring Drug Resistance.ACS chemical biology · 2019Article
- Structural and binding insights into HIV-1 protease and P2-ligand interactions through molecular dynamics simulations, binding free energy and principal component analysis.Journal of molecular graphics & modelling · 2019Article
- Molecular Determinants of Epistasis in HIV-1 Protease: Elucidating the Interdependence of L89V and L90M Mutations in Resistance.Biochemistry · 2019Article
- Structural Adaptation of Darunavir Analogues against Primary Mutations in HIV-1 Protease.ACS infectious diseases · 2019Article
- Accelerated Molecular Dynamics Simulation for Helical Proteins Folding in Explicit Water.Frontiers in chemistry · 2019Article
- Evolutionary footprint of epistasis.PLoS computational biology · 2018Article
- Exploring the Reasons for Decrease in Binding Affinity of HIV-2 Against HIV-1 Protease Complex Using Interaction Entropy Under Polarized Force Field.Frontiers in chemistry · 2018Article
- Elucidating the Interdependence of Drug Resistance from Combinations of Mutations.Journal of chemical theory and computation · 2017Article
- Sequence, Structural Analysis and Metrics to Define the Unique Dynamic Features of the Flap Regions Among Aspartic Proteases.The protein journal · 2017Review
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Abstract
In the present work, the binding of inhibitor TMC114 (darunavir) to wild-type (WT), single (I50V) as well as double (I50L/A71V) mutant HIV-proteases (HIV-pr) was investigated with all-atom molecular dynamics (MD) simulations as well as molecular mechanic-Poisson-Boltzmann surface area (MM-PBSA) calculation. For both the apo and complexed HIV-pr, many intriguing effects due to double mutant, I50L/A71V, are observed. For example, the flap-flap distance and the distance from the active site to the flap residues in the apo I50L/A71V-HIV-pr are smaller than those of WT- and I50V-HIV-pr, probably making the active site smaller in volume and closer movement of flaps. For the complexed HIV-pr with TMC114, the double mutant I50L/A71V shows a less curling of the flap tips and less flexibility than WT and the single mutant I50V. As for the other previous studies, the present results also show that the single mutant I50V decreases the binding affinity of I50V-HIV-pr to TMC, resulting in a drug resistance; whereas the double mutant I50L/A71V increases the binding affinity, and as a result of the stronger binding, the I50L/A71V may be well adapted by the TMC114. The energy decomposition analysis suggests that the increase of the binding for the double mutant I50L/A71V-HIV-pr can be mainly attributed to the increase in electrostatic energy by -5.52 kacl/mol and van der Waals by -0.42 kcal/mol, which are canceled out in part by the increase of polar solvation energy of 1.99 kcal/mol. The I50L/A71V mutant directly increases the binding affinity by approximately -0.88 (Ile50 to Leu50) and -0.90 (Ile50' to Leu50') kcal/mol, accounting 45% for the total gain of the binding affinity. Besides the direct effects from the residues Leu50 and Leu50', the residue Gly49' increases the binding affinity of I50L/A71V-HIV-pr to the inhibitor by -0.74 kcal/mol, to which the electrostatic interaction of Leu50's backbone contributes by -1.23 kcal/mol. Another two residues Ile84 and Ile47' also increase the binding affinity by -0.22 and -0.29 kcal/mol, respectively, which can be mainly attributed to van der Waals terms (ΔT(vdw) = -0.21 and -0.39 kcal/mol).
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