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Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.

ABSTRACT: BACKGROUND: Over the last decades, a vast structural knowledge has been gathered on the HIV-1 protease (PR). Noticeably, most of the studies focused the B-subtype, which has the highest prevalence in developed countries. Accordingly, currently available anti-HIV drugs target this subtype, with considerable benefits for the corresponding patients. RESULTS: Herein, we used molecular dynamics simulations to investigate the role of this polymorphism on the interaction of PR with six of its natural cleavage-sites substrates. CONCLUSIONS: With multiple approaches and analyses we identified structural and dynamical determinants associated with the changes found in the binding affinity of the M36I variant. This mutation influences the flexibility of both PR and its complexed substrate. The observed impact of M36I, suggest that combination with other non-B subtype polymorphisms, could lead to major effects on the interaction with the 12 known cleavage sites, which should impact the virion maturation.

SUBMITTER: Costa MG

PROVIDER: S-EPMC4243740 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.

Costa Mauricio G S MG Benetti-Barbosa Técio G TG Desdouits Nathan N Blondel Arnaud A Bisch Paulo M PM Pascutti Pedro G PG Batista Paulo R PR

BMC genomics 20141027

<h4>Background</h4>Over the last decades, a vast structural knowledge has been gathered on the HIV-1 protease (PR). Noticeably, most of the studies focused the B-subtype, which has the highest prevalence in developed countries. Accordingly, currently available anti-HIV drugs target this subtype, with considerable benefits for the corresponding patients.<h4>Results</h4>Herein, we used molecular dynamics simulations to investigate the role of this polymorphism on the interaction of PR with six of ...[more]

PMID: 25573486

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Project description:HIV-1 protease (HIV-1-pr) plays an important role in viral replication and maturation, making it one of the most attractive targets for anti-retroviral therapy. To design new effective inhibitors able to combat drug resistance in mutant HIV-1-pr variants, it is essential to gain further understanding about the mechanisms by which the recently proposed inhibitors deactivate the mutant HIV-1-pr variants. In the present work, we explored the interactions between two P2-ligands (DRV, and one new derivative, 4UY) with wild type (WT) and two multiple mutant HIV-1-pr variants (p20 and p51) with all atom molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA). The trajectories of MD simulations show that both 4UY and DRV primarily bind with the active sites, flap and 80s loop regions of HIV-1-pr variants through either hydrogen bonds or hydrophobic interactions. More hydrogen bonds and hydrophobic interactions were located for 4UY/HIV-1-pr complexes than for DRV/HIV-1-pr counterparts. More importantly, 4UY was found to have an extra hydrogen bond with the backbone of Gly48' in the flap region of the HIV-1-prs. The flap tip-tip distance (I50-I50') and flap tip-active site distance (I50-D25 and I50'-D25') indicate that the flaps turn more closed in 4UY bound HIV-1-prs than DRV bound ones, and the former also have more compact hydrophobic cavities than the latter. Further, the vector projections from PCA indicate that 4UY/DRV inhibitor binding projects the closing of flap in HIV-1-pr variants. In line with the above trajectory analysis, the thermodynamics calculation with MM-PBSA method suggests much stronger binding affinity for 4UY/HIV-1-pr than DRV/HIV-1-pr by 4.3-6.4 kcal/mol. Although p20 and p51 also induce weaker binding due to multiple mutants for 4UY inhibitor by 1.9-1.8 kcal/mol, their bindings to the new P2 ligand (4UY) are indeed significantly enhanced as compared to DRV. The thermodynamic components responsible for the binding differences and the contribution from key residues to the binding were also discussed in detail.

Dataset Information

Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.

Publications

Impact of M36I polymorphism on the interaction of HIV-1 protease with its substrates: insights from molecular dynamics.

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