Doctoral seminar

Molecular Modeling of HIV--1 Integrase--DNA Quadruplex Complex:
HIV–1 integrase catalyzes the insertion of proviral DNA into the human genome in a two–step reaction involving an initial nucleotide end priming followed by a covalent integration step. 93del, a G–DNA aptamer, was shown in an earlier study to bind and inhibit HIV–1 integrase at nanomolar range. The nucleotide had also been revealed to adopt a remarkably stable quadruplex structure in the presence of potassium cations. The enzyme contains a lysine–rich positively charged cavity that bears structural and electrostatic complementarity to negatively–charged tetrad arrangement of 93del. This had been proposed to be responsible for the observed binding interaction between the two. Experimental procedures have however not been successful at confirming this partly because of the inherent challenges involved in obtaining crystals of the complex, and because the atomistic detail necessary to adequately explain the affinity is currently beyond the reach of conventional experimental methods. This study presents the initial results obtained from the molecular dynamics simulation of HIV1–integrase–93del interaction using AMBER Barcelona parambsc0 forcefield and an explicit water model. A complex of the two molecules was generated using a protein-DNA docking program. The entire system was simulated in a cubic box coupled to a thermostat with periodic boundary condition implemented across its edges. After analyzing the trajectories the complex was found to remain stable throughout the evolution with more residues, both of integrase and the quadruplex, involved in the binding interaction at the end of the simulation than at the start. The analysis further suggested that the amino residues previously missing from the initial crystallographic data of integrase were crucial in driving the interaction.

Speaker: Olujide Olubiyi

Date: Monday, December 7, 2009

Time: 16:15

Location: Seminar Room 200, Jülich Supercomputing Centre, Forschungszentrum Jülich, 52425 Jülich