Molecular dynamics and free energy analysis of neuraminidase–ligand interactions

We report molecular dynamics calculations of neuraminidase in complex with an inhibitor, 4‐amino‐2‐deoxy‐2,3‐didehydro‐N‐acetylneuraminic acid (N‐DANA), with subsequent free energy analysis of binding by using a combined molecular mechanics/continuum solvent model approach. A dynamical model of the complex containing an ionized Glu119 amino acid residue is found to be consistent with experimental data. Computational analysis indicates a major van der Waals component to the inhibitor‐neuraminidase binding free energy. Based on the N‐DANA/neuraminidase molecular dynamics trajectory, a perturbation methodology was used to predict the binding affinity of related neuraminidase inhibitors by using a force field/Poisson‐Boltzmann potential. This approach, incorporating conformational search/local minimization schemes with distance‐dependent dielectric or generalized Born solvent models, correctly identifies the most potent neuraminidase inhibitor. Mutation of the key ligand four‐substituent to a hydrogen atom indicates no favorable binding free energy contribution of a hydroxyl group; conversely, cationic substituents form favorable electrostatic interactions with neuraminidase. Prospects for further development of the method as an analysis and rational design tool are discussed.