Studying how molecular dynamics can accelerate biochemical investigations can both help in fighting particular diseases and, more broadly, offer opportunities be prepared as novel biological threats emerge. This case study of simulation investigations of a flu proton channel highlights the importance of studying water networks associated with proteins. Influenza B virus matrix protein 2 (BM2), a tetrameric transmembrane proton channel found in one type of flu virus, constitutes a possible antiviral target of interest, as revealed by reverse genetics experiments. At low pH, BM2 exists in an open state, facilitating proton transport; meanwhile, at high pH, BM2 exists in a closed state, in which proton transport is diminished. The Hong research group has obtained nuclear magnetic resonance (NMR) structures of BM2 in its open and closed states. The residues lining the BM2 transmembrane pore are mostly hydrophilic. Water can facilitate proton transport by enabling proton hopping from one water molecule to the next via a Grotthuss mechanism: therefore, investigating the structure and connectivity of the water network in BM2’s different states could help articulate requirements for proton transport. Though analyzing BM2’s water network could facilitate studying proton transport, NMR work has not yet been able to directly investigate water network connectivity.<br/><br/>Simulations can provide atomistic detail on protein and water dynamics, offering exquisite spatiotemporal resolution. All-atom molecular dynamics simulations of BM2 were carried out, in which the BM2 open state and closed state NMR structures were simulated. Hydrogen bonding analyses of simulations revealed that the closed state exhibits more frequent interruptions in water network hydrogen bonding connectivity along the channel than the open state does: such disconnections could impede proton transport. Simulations thus indicate that the open state of BM2 enables a more connected water hydrogen bonding network to exist in the transmembrane pore than does the closed state of BM2. These findings help shed light on structural features of water networks which could facilitate proton transport. This work may help both understand structural requirements for a BM2 inhibitor and, more broadly, elucidate how computation can study water networks in intricate detail in collaboration with experiment, an approach which may be transferable to fighting other diseases.

Viral videos: Molecular dynamics simulations of an influenza virus proton channel can yield transferable lessons

ACS Spring Meeting 2021

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