Towards a better semiquantitative estimation of binding constants: molecular dynamics exploration of the conformational behavior of isolated sialyllactose and sialyllactose complexed with influenza A hemagglutinin

Abstract

The binding of influenza A virus is mediated by the attachment of the viral hemagglutinin (HA) to sialic acids (Sia) which are components of virus receptors. Molecular dynamics simulations were applied to study the conformational behavior of isolated sialyllactose (SL) and SL complexed with HA in order to achieve a deeper understanding of the process of binding. If a flexible molecule binds to a protein the binding process must select one conformation from the conformational ensemble. The process of freezing the degrees of freedom of the ligand implies a decrease in entropy of the oligosaccharide on binding. The comparison of the conformational behavior of isolated SL and the SL-HA complex showed that the conformational freedom of SL in the bound state is considerably reduced. The specific conformation which has to be frozen out to form the complex with HA, however, is populated in the free state for all functional groups of SL, which is essential for the process of binding. Molecular dynamics (MD) simulations indicate that for the HA-SL complex the strongest decrease in entropy should occur when freezing out the desired conformation of the carboxyl group, both glycosidic linkages and the pendant groups of galactose and glucose.