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Inhibition of the activity of HIV-1 protease through antibody binding and mutations probed by molecular dynamics simulations.

ABSTRACT: HIV-1 protease is an essential enzyme in the life cycle of the HIV-1 virus. The conformational dynamics of the flap region of the protease is critical for the ligand binding mechanism, as well as for the catalytic activity. The monoclonal antibody F11.2.32 raised against HIV-1 protease inhibits its activity on binding. We have studied the conformational dynamics of protease in its free, inhibitor ritonavir and antibody bound forms using molecular dynamics simulations. We find that upon Ab binding to the epitope region (residues 36-46) of protease, the overall flexibility of the protease is decreased including the flap region and the active site, which is similar to the decrease in flexibility observed by inhibitor binding to the protease. This suggests an allosteric mechanism to inhibit protease activity. Further, the protease mutants G40E and G40R are known to have decreased activity and were also subjected to MD simulations. We find that the loss of flexibility in the mutants is similar to that observed in the protease bound to the Ab/inhibitor. These insights highlight the role played by dynamics in the function of the protease and how control of flexibility through Ab binding and site specific mutations can inhibit protease activity.

SUBMITTER: Badaya A

PROVIDER: S-EPMC7098958 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Inhibition of the activity of HIV-1 protease through antibody binding and mutations probed by molecular dynamics simulations.

Badaya Apoorva A Sasidhar Yellamraju U YU

Scientific reports 20200326 1

HIV-1 protease is an essential enzyme in the life cycle of the HIV-1 virus. The conformational dynamics of the flap region of the protease is critical for the ligand binding mechanism, as well as for the catalytic activity. The monoclonal antibody F11.2.32 raised against HIV-1 protease inhibits its activity on binding. We have studied the conformational dynamics of protease in its free, inhibitor ritonavir and antibody bound forms using molecular dynamics simulations. We find that upon Ab bindin ...[more]

PMID: 32218488

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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

Inhibition of the activity of HIV-1 protease through antibody binding and mutations probed by molecular dynamics simulations.

Publications

Inhibition of the activity of HIV-1 protease through antibody binding and mutations probed by molecular dynamics simulations.

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