| Abstract
| - HIV-1 reverse transcriptase (RT) is an important target for drugs used in the treatment of AIDS.Drugs known as non-nucleoside RT inhibitors (NNRTI) appear to alter the structural and dynamical propertiesof RT which in turn inhibit RT's ability to transcribe. Molecular dynamics (MD), principal component analysis(PCA), and binding free energy simulations are employed to explore the dynamics of RT and its interactionwith the bound NNRTI nevirapine, for both wild-type and mutant (V106A, Y181C, Y188C) RT. These threemutations commonly arise in the presence of nevirapine and result in resistance to the drug. We show thata bound NNRTI hinders the motion of almost all RT amino acids. The mutations, located in thenon-nucleoside RT inhibitor binding pocket, partially restore RT flexibility. The binding affinities calculatedby molecular mechanics/Poisson−Boltzmann surface accessibility (MM-PBSA) show that nevirapine interactsstronger with wild-type RT than with mutant RT. The mutations cause a loss of van der Waals interactionsbetween the drug and the binding pocket. The results from this study suggest that a good inhibitor shouldefficiently enter and maximally occupy the binding pocket, thereby interacting effectively with the aminoacids around the binding pocket.
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