Nevill Mottt Hall
Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Jakkur Campus, Bangalore 560064

Administrative Contact:

K Venkatesh
Programme Assistant

Email: dmwater@jncasr.ac.in

Tel: 080-22082899
Fax: 080-2208 2906

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Regular JNC Shuttle Bus Timings:

January 9:
From IISc 9:00 a.m, 10:15 a.m.

January 10:
From IISc: 8:30 a.m, 10:00 a.m.

Discussion Meeting on
Water and Aqueous Solutions

January 9 - 10, 2015

Molecular Dynamics Simulations of Ligand-induced Flap
Closing in HIV-1 Protease Approach X-ray Resolution:
Establishing the Role of Bound Water in the Flap Closing Mechanism

Sanjib Senapati
Department of Biotechnology, Indian Institute of Technology Madras,
Chennai 600036, India

E-mail: sanjibs@iitm.ac.in

 Abstract: The necessity of understanding the detailed mechanism of flap dynamics in designing HIV-1 protease inhibitors is immense. Crystal structures have provided a static overview of various conformations of the enzyme, but the existence of strong interplay among various conformations came to the fore only after dynamics studies. In the talk, I will elucidate the mechanistic aspects of HIV-1 protease flap closing upon binding inhibitors, from the results of all-atom molecular dynamics simulations. The unrestrained simulations reproduced not only the correct inhibitor-bound protease closed structures, but also the structural water molecule which is seen in all protease-ligand X-ray structures. The study demonstrates that the hydrophobic clustering is not a strong enough stimulus to induce protease flap closing, as previously believed. The structural water plays a critical role in flap closing dynamics by destabilizing the hydrophobic clusters and subsequently by mediating the flap-ligand interactions. Our results corroborate well with prior simulation and experimental findings and, at the same time, provide a molecular level description of the HIV-1 protease flap closing mechanism which can be crucial in the understanding of drug-receptor interactions.