Evaluating Associations with the Mechanism of the K65R Mutation in HIV-1 Reverse Transcriptase Using Computational Molecular Docking

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) are common antiretroviral HIV medications, targeting the function of reverse transcriptase (RT), a protein designed to transcribe viral RNA into DNA. An emerging problem is the development of resistance against such medications. For example, the K65R mutation in RT has been shown to decrease the binding affinity of RT to the NRTI tenofovir, while conserving affinity to tenofovir’s nucleotide analog, adenosine. This has been associated with the decreased distance between the guanidinium planes of residues 65 (R65) and 72 (R72) and, alternatively, with the increased distance between tenofovir and DNA already bound to RT. These theories have never been tested. This study aims to evaluate these theories through computational methods. Mutations were generated within the β3 β4 loop of K65R-mutant reverse transcriptase (accessed from the Protein Data Bank). For each mutation introduced, data was recorded on the distance between the R65 and R72 guanidinium planes, as well as the distance between RT-bound ligand and RT-bound DNA. In addition, the binding affinity of ligands tenofovir and adenosine to RT was calculated through the docking software Autodock Vina. After 95 mutations, linear correlations indicated that the binding affinity of tenofovir to R65/R72 increased with the decreased distance between the guanidinium planes of R65/R72, contrary to previous literature. In addition, a significant, increasing relationship was seen between binding affinity and the increased distance between either tenofovir and adenosine and RT-bound DNA, challenging the previously postulated association of this distance with the mechanism of the K65R mutation.

Keywords: K65R mutation, antiretroviral resistance, reverse transcriptase, HIV-1, molecular docking

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