291889 Prediction of Influenza A Virus Hemagglutinin Binding Sites Using Dynamics Perturbation Analysis

Monday, October 29, 2012
Hall B (Convention Center )
Chantel Gaudet, Department of Chemical Engineering, University of Pittsburgh, Rochester, NY; Department of Chemical Engineering and Department of Mathematics, University of Rochester, Rochester, NY, David Dreisigmeyer, Center for Economic Studies, USPTO and US Census Bureau, Alexandria, VA and Gilles Clermont, Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA

We determined the amino acid residues responsible for the species specific binding of the Hemagglutinin (HA) protein in the Influenza A virus using dynamic perturbation analysis (DPA).  DPA identifies the regions of greatest change in protein conformational distribution by measuring relative entropy of minimal surface perturbations in a normal-modes model.  Those regions may theoretically indicate biological activity such as ligand binding in HA proteins.  To compute the normal modes across a set of homologous HA proteins, we modeled each HA as an isotropic elastic network with springs linking every alpha-carbon between protein residues, using published 3D crystallographically-determined HA structures.  Calibrated using known ligand binding sites, the DPA algorithm successfully predicted the primary and secondary binding sites of HA to sialic acid residues of human respiratory epithelial cells, as well as other potential regions of interest.  This method can be applied to other proteins of the influenza genome for which drug targets currently do not exist.

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