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

Apoorva Badaya,Yellamraju U Sasidhar

doi:10.1038/s41598-020-62423-y

Apoorva Badaya, Yellamraju U Sasidhar

Open Access

https://doi.org/10.1038/s41598-020-62423-y

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Journal: Scientific Reports	Publication Date: Mar 26, 2020
Citations: 20	License type: open-access

Affiliation: Indian Institute of Technology Bombay

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.

Highlights

(P36–45), it is suggested that F11.2.32 could cause antibody induced structural changes in the protease and this may perhaps inhibit the proteolytic activity of the protease[11]
We find from our simulation results that the mutant proteases too show quenching in their positional fluctuations, which is similar to the quenching observed in Ab-bound and inhibitor-bound proteases
We calculated and compared the Cα-Cα distance between the Ile-50 residues present at the tip of the flaps of the HIV-1 protease monomers (50Cα(Ile)chainA-50′Cα(Ile)chainB), in the WT-free, Ab-bound, RIT-bound and mutant (G40R and G40E) protease simulations (Fig. 1(iii)(B))

Summary

Introduction

(P36–45), it is suggested that F11.2.32 could cause antibody induced structural changes in the protease and this may perhaps inhibit the proteolytic activity of the protease[11]. The flexibility of the flap and other functionally important regions of the HIV-1 protease are examined upon antibody binding by molecular dynamics simulations to understand the role of dynamics in inhibiting the enzyme activity. Our studies suggest that upon antibody and inhibitor binding, the overall dynamics of the protease are quenched, including flap and active site regions. The open and close mechanism of the flap is restricted, which in turn may affect the substrate binding to the active site Such modulations may affect the functional activity of the HIV-1 protease. We further studied the correlation of motions in the protease to understand the protein dynamics and conformational changes in WT-free, Ab-bound, RIT-bound and mutant proteases. This study points to a plausible method for allosteric drug control

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