Influenza is one of the most well-known viruses, yet much remains to be discovered. Glycans, the ubiquitous polysaccharides that decorate the surface of influenza membrane proteins, play a complex part in influenza's daily functions. Glycans are known to modulate influenza's transmissibility, virulence, electrostatics, sterics, cooperativity, drug binding, dynamics, antibody response, and immune evasion, amongst other aspects, but their exact role is not always well-understood. Additionally, experimental influenza work is challenging to deconvolute due to complex and overlapping interactions, and due to influenza’s mutability. These challenges can be bypassed by interrogating these systems computationally. To examine how glycan and influenza strain differences affect small molecule binding kinetics to influenza, we created <i>in silico </i>systems of neuraminidase from avian influenza (H5N1 A/Vietnam/1203/2004) and swine flu (H1N1 A/California/04/2009) with experimentally-derived, biologically-relevant glycoprofiles. We then ran Brownian dynamics association rate studies of six biologically-relevant small molecules known to bind to neuraminidase: sialic acid, oseltamivir (Tamiflu), zanamivir (Relenza), peramivir (Rapivab), laninamivir, and DANA. Through these simulations, we found that glycans can hinder small molecule access to neuraminidase binding sites. These results increase our understanding of how the viral glycoprofile influences molecular association.

How does glycosylation affect small molecule binding on influenza? Roles of electrostatics and sterics examined through Brownian dynamics simulations

2019 Fall National Meeting

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