Neuraminidase (NA), a homotertameric viral surface protein, is essential to the influenza virus’ replication cycle. NA’s catalytic function is to cleave terminal sialic acid moieties from host cell surface receptors, thus enabling nascent viral release. An effective method for preventing the proliferation of the virus has been to use small molecule inhibitors, including widely prescribed oseltamivir (Tamiflu<sup>®</sup>). However, some strains of mutated influenza like H274Y have displayed resistance to NA inhibitors. To better understand how these ligands interact with neuraminidase, we simulated the complete binding trajectories of sialic acid to the wild-type NA and oseltamivir to the wild-type NA utilizing Brownian Dynamics (BD) and Molecular Dynamics (MD) for the diffusional approach and close-range interactions respectively. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) free energy calculations were employed in order to identify specific binding pathways and areas of binding favorability for both complexes. Additional trajectory-specific analysis further elucidated the ligand-residue interactions that develop these pathways. Work done thus far has revealed a set of six residues that form a channel-like structure. The channel interacts with hydroxyl groups on sialic acid’s aliphatic chain, thus orienting the ligand so that the carboxylate can form salt bridges with active site residues. The lack of similar functionality on oseltamivir’s aliphatic chain is a possible explanation for the pathway’s decreased favorability in the NA/OST complex.

Analysis of MM/GBSA free energy calculations to investigate the binding pathways of neuraminidase

253rd National Meeting (2017)

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