Comparison of Multiple Molecular Dynamics Trajectories Calculated for the Drug-Resistant HIV-1 Integrase T66I/M154I Catalytic Domain

¹ The Genetics Company
² University of Houston
³ Emisphere Technologies, Inc.

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

Submitted on July 22, 2004
Revised on August 24, 2004
Accepted on 21 December 2004

	Abstract

HIV-1 integrase (IN) is an essential enzyme for the viral replication and an interesting target for the design of new pharmaceuticals for multi-drug therapy of AIDS. Single and multiple mutations of IN at residues T66, S153 or M154 confer degrees of resistance to several inhibitors that prevent the enzyme from performing its normal strand transfer activity. Four different conformations of IN were chosen from a prior molecular dynamics (MD) simulation on the modeled IN T66I/M154I catalytic core domain as starting points for additional MD studies. The aim of this paper is to understand the dynamic features that may play roles in the catalytic activity of the double mutant enzyme in the absence of any inhibitor. Moreover, we want to verify the influence of using different starting points on the MD trajectories and associated dynamical properties. By comparison of the trajectories obtained from these MD simulations we have demonstrated that the starting point does not affect the conformational space explored by this protein and that the time of the simulation is long enough to achieve convergence for this system.

Key Words: conformational sampling, drug resistance, essential dynamics, molecular dynamics

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