Insight into HIV-1 reverse transcriptase–aptamer interaction from molecular dynamics simulations

Abstract

Human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is considered to be one of the key targets for antiviral drug therapy. The emergence of the aptamers as potential inhibitors against HIV-1 reverse transcriptase has attracted the attention of the scientific community because these macromolecules can effectively inhibit HIV-1 RT with between micromolar to picomolar concentrations. However, it is not clear how aptamers interact with HIV-1 RT. We have undertaken a molecular dynamics (MD) study in order to gain a keen insight into the conformational dynamics of HIV-1 RT on the formation of a complex with an aptamer or DNA substrate. We have therefore employed three separate models: apo HIV-1 RT, HIV-1 RT with a bound RNA aptamer, and HIV-1 RT with a bound DNA substrate. The results show that HIV-1 RT complex with an aptamer was more stable than that with DNA substrate. It was found that the aptamer interacted with HIV-1 RT in a fingers-and-thumb-closed conformation, at the bound at the nucleic acid substrate binding site. We identified key residues within the HIV-1 RT-aptamer complex in order to help design, develop, and test a new aptamer based on therapies in the future.

The Bound Structures of 17β‐Estradiol‐Binding Aptamers

“…MD can provide insight into the molecular interactions involved in binding, binding affinity, important binding positions, minimal binding sequence, mutations to enhance binding, and the best places to tether newly‐defined aptamers onto electrodes, nanoparticles, nanotubes and dyes. Yet, few computational studies exist investigating aptamer‐target interactions at a molecular level . Aeksiri et al .…”

“…Yet, few computational studies exist investigating aptamer‐target interactions at a molecular level . Aeksiri et al . used MD simulations to provide critical insight into the interaction of an aptamer with human immunodeficiency virus‐1 reverse transcriptase (HIV‐1 RT), a key target for antiviral drug therapy.…”

“…The aptamer was known to effectively inhibit HIV‐1 RT, but the interaction mechanisms were not understood until the work of Aeksiri et al. . Similarly, Pagano et al .…”

Oligonucleotide aptamers: promising and powerful diagnostic and therapeutic tools for infectious diseases

“…HIV-1 RT catalyzes the conversion of the single-stranded genomic viral RNA into double-stranded proviral DNA, which in turn is integrated into the host genome. 87 To date, numerous RNA or DNA aptamers against HIV-1 RT have been generated, and their application to the inhibition of viral replication has been investigated. [88][89][90][91][92][93][94][95] Among these anti-RT aptamers, an ssDNA aptamer generated by capillary electrophoresis-SELEX and 2 -deoxy-2 -fluoroarabinonucleotide (FANA) aptamer FA1 can strongly bind HIV-1 RT, with low picomolar dissociation constants.…”

Structural insights into type I and type II of nsp4 porcine reproductive and respiratory syndrome virus (nsp4 PRRSV) by molecular dynamics simulations

“…Moreover, it has been widely used to study the effect of single or multiple mutations. For example, it was applied to several proteins such as l-alanine dehydrogenase [28], protein tyrosine phosphatase 1B [29], HIV-1 RT [30] and RAS-relate C3 botulinum toxin substrate 1(RAC1) [31]. Therefore, MD simulations have been used for extensive analysis, and the results often help to explain the experimental data.…”