Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Thursday Speaker Abstracts

INFLUENZA HEMAGGLUTININ-MEDIATED MEMBRANE FUSION: AN ALL- ATOM MOLECULAR DYNAMICS STUDY Mahmoud Moradi 1 ; Ugochi Isu 1 ; 1 University of Arkansas, Chemistry and Biochemistry, Fayetteville, Arkansas, USA The influenza hemagglutinin (HA) fusion protein is a canonical example of a viral fusion protein that mediates the cell entry of a membrane-enveloped virus. Since its structure was solved about four decades ago, extensive structural studies have aimed at deciphering the relationship between HA conformational changes and its ability to fuse lipid bilayers. We have used an extensive set of all-atom molecular dynamics simulations in conjunction with statistical mechanics based enhanced sampling techniques and ensemble-based simulation methods to visualize various conformational changes of the HA2 protein involved in the fusion mechanism. Here we focus on the large-scale conformational changes of HA2 in various stages that are primarily triggered by a change in the pH. In the first stage, the unstructured B loop of HA2 protein folds into a coiled- coil motif, extending the existing coiled-coil motif of HA2. Our simulations thus provide the first physics-based model of the elusive extended intermediate of HA2, where the fusion peptide inserts into the host cell membrane. The second stage involves partial unfolding of the central helix of HA2, which can be triggered by the protonation of a single histidine residue according to our simulations. Upon the formation of a hinge region, our simulations reveal that HA2 chain of hemagglutinin can bend. The HA2 conformational changes bring the membranes in close proximity, resulting in fusion of the viral envelope and the endosomal membrane. The novel computational methodology used in this work provides a detailed description of the mechanism of HA fusion protein and elucidates that how the protonation of a few amino acids can trigger the complex conformational changes of the HA2 protein, which effectively catalyze the fusion process.

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