Large Scale Conformational Dynamics of the HIV-1 Integrase Core Domain and its Catalytic Loop Mutants

¹ University of Delaware
² University of Houston
³ University of California at Davis

^* To whom correspondence should be addressed. E-mail: duan{at}ucdavis.edu.

Submitted on December 21, 2004
Revised on January 20, 2005
Accepted on 4 February 2005

	Abstract

HIV-1 integrase is one of the three essential enzymes required for viral replication and has great potential as a novel target for anti-HIV drugs. Although tremendous efforts have been devoted to understanding this protein, the conformation of the catalytic core domain around the active-site, particularly the catalytic loop over-hanging the active-site, is still not well characterized by experimental methods due its high degree of flexibility. Recent studies have suggested that this conformational dynamics is directly correlated to enzymatic activity, but the details of this dynamics is not known. In this study, we conducted a series of extended-time molecular dynamics simulations and locally enhanced sampling simulations of the wild-type and three loop-hinge mutants to investigate the conformational dynamics of the core domain. A combined total of > 480-ns of simulation data were collected which allowed us to study the conformational changes that were not possible to observe in the previously reported short-time MD simulations. Among the main findings are: a major conformational change (>20 Å) in the catalytic loop which revealed a gating-like dynamics, and a transient intra-loop structure which provided a rationale for the mutational effects of several residues on the loop including Q148, P145, and Y143. Further, clustering analyses have identified seven major conformational states of the wild-type catalytic loop. Their implications for catalytic function and ligand interaction are discussed. The findings reported here provide a detailed view of the active-site conformational dynamics and should be useful for structure-based inhibitor design for integrase.

Key Words: AMBER ff03, HIV-1 Integrase, drug design, locally enhanced sampling, molecular dynamics, structure-function relationship

This article has been cited by other articles:

				C. N. Alves, S. Marti, R. Castillo, J. Andres, V. Moliner, I. Tunon, and E. Silla A Quantum Mechanic/Molecular Mechanic Study of the Wild-Type and N155S Mutant HIV-1 Integrase Complexed with Diketo Acid Biophys. J., April 1, 2008; 94(7): 2443 - 2451. [Abstract] [Full Text] [PDF]

				K. Shimura, E. Kodama, Y. Sakagami, Y. Matsuzaki, W. Watanabe, K. Yamataka, Y. Watanabe, Y. Ohata, S. Doi, M. Sato, et al. Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137) J. Virol., January 15, 2008; 82(2): 764 - 774. [Abstract] [Full Text] [PDF]

				N. Nunthaboot, S. Pianwanit, V. Parasuk, J. O. Ebalunode, J. M. Briggs, and S. Kokpol Hybrid Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulations of HIV-1 Integrase/Inhibitor Complexes Biophys. J., November 15, 2007; 93(10): 3613 - 3626. [Abstract] [Full Text] [PDF]

				J. Puglia, T. Wang, C. Smith-Snyder, M. Cote, M. Scher, J. N. Pelletier, S. John, C. B. Jonsson, and M. J. Roth Revealing Domain Structure through Linker-Scanning Analysis of the Murine Leukemia Virus (MuLV) RNase H and MuLV and Human Immunodeficiency Virus Type 1 Integrase Proteins J. Virol., October 1, 2006; 80(19): 9497 - 9510. [Abstract] [Full Text] [PDF]