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.The HIV-1 protease belongs to the family of aspartyl protease. It cleaves the newly synthesized polyproteins, which is the vital step to create the mature protein components of an infectious HIV-1 virus 1 . Thus, HIV-1 protease is an essential enzyme in the life-cycle of the HIV-1 virus and a potential target for the structure-based drug design. There are several commercial drugs available in the market against the HIV-1 protease. The success rate of these drugs is low due to the occurrence of drug-resistant mutations in the HIV-1 protease 2 . For example, the thermodynamic integration (TI) and MD simulation studies by Chen and his group suggested that there is a change in the shape and conformation of the binding pocket upon certain drug-resistant mutations and this consequently reduces the binding affinity of inhibitor 3 . Also, conventional method of drug delivery targets active sites and many enzymes with related function may have very similar active sites. This may cause adverse side-effects. Therefore, there is a requirement to generate new generation drugs that can function away from active-site and these are allosteric drugs 4-7 . To identify a new target on HIV-1 protease, there is a need to understand the complete structure and dynamics of HIV-1 protease to inhibits its enzymatic activity. The HIV-1 protease is a homodimeric enzyme with each monomer comprising of 99 amino-acid residues 8 . The active site (residues Asp25, Thr26 and Gly27 from both chains A and B) of the protease is covered by two flaps (residues 43-58) from each chain 9,10 . F11.2.32 is a monoclonal antibody (mAb) raised against the HIV-1 protease. The peptide P36-46 ( 36 MNLPGRWKPKM 46 ) corresponding to the epitope/elbow region of the protease binds to the complementarity determining regions (CDRs) of ...

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