SUNY at Albany
June 19-23, 2001
Computer Aided Study of Ligand Binding to with Catalytic Domain of Avian Sarcoma Virus Integrase
We report here 500 pico seconds (ps) molecular dynamics (MD) simulation results on two molecules of 4-acetylamino-5-hydroxy naphthalene 2-7disulfonic acid (Y-3) in the catalytic domain (residues 54-199) of avian sarcoma virus integrase (ASV-IN) dimer. Starting model was obtained on the basis of PDB coordinates for the monomer. Two molecules of Y3 were docked in the active cavity of the dimer using in house package IMF. Two loops Gly54-Gln62 (L1) and Trp138-Met155 (L2) from two monomers making a compact basket type structure around the Y3 dimer. Energy minimization (EM) and MD simulation were carried out using Sander?s module of AMBER 5.0 with all atom force field. Analysis of the ligand protein interaction showed that interaction amongst R1 and R3 of Y3A and Y3B with amino acid side chains of Gln62 and Lys119, backbone N atoms of Gly54, Leu55, Gly56, Pro57 and loop residues Gln153, Ala154 and Met155 stabilized the complex. Ile60 and Ile146 had hydrophobic contact interactions with R2 and R4. We also monitored perturbative changes in the protein. Higher flexibility of the loops: between b4-a3 and a4-a5 facilitated these interactions.
ASV-IN cannot function as a monomer because of its more open conformation. It is necessary to have at least a dimer for creation of the catalytic cavity. The two molecules of Y3A and Y3A interact with each other by stacking interaction, which is facilitated by their naphthalene base. The dimer had a size suitable for occupying the active cavity. The cavity had basic, polar neutral or hydrophobic amino acid side chains. Hence, ligands with number of highly acidic groups as SO3 and few hydrophobic groups (as Me) are ideal. Higher activity of Y3 compared to Y1, Y2 and Y4 is because of presence of two SO3 groups in contrast to one in Y1, Y2 and Y4.
To probe further into the role of ligand in perturbative changes in IN, MD simulations of loops L1 and L2 was carried out in vacuum, in water and in organic solvent(methanol) using AMBER 6.0 and Monte Carlo (BOSS 4.1) method. The details will be discussed in the presentation.
V.Kothekar, S. Shankar and A. Kumar
Department of Biophysics, All India Institute of Medical Sciences, New Delhi-110029, India