Abstract
The conformational change associated with membrane fusion for Influenza A Hemagglutinin is investigated with a model based upon pre- and post-fusion structures of the HA2 component. We employ computational methods based on the potential energy landscape framework to obtain an initial path connecting these two end points, which provides the starting point for refinement of a kinetic transition network. Here we employ discrete path sampling, which provides access to the experimental time and length scales via geometry optimization techniques to identify local minima and the transition states that connect them. We then analyse the distinct phases of the predicted pathway in terms of structure and energetics, and compare with available experimental data and previous simulations. Our results provide the foundations for future work, which will address the effect of mutations, changes in pH, and incorporation of additional components, especially the HA1 chain and the fusion peptide.
Highlights
The influenza virus is a major cause of morbidity and mortality in humans
The local minima and transition states obtained in producing the initial connected pathway constitute the first entries in a kinetic transition network (Rao and Caflisch, 2004; Nóe and Fischer, 2008; Prada-Gracia et al, 2009; Wales, 2010) (KTN)
The initial path contains 4,326 transition states (8,653 stationary points) and the fastest path after refinement has reduced to 3,420 transition states (6,841 stationary points). This simplification is typical of previous results for biomolecules, where the number of steps in the initial path usually decreases by 20% or more when discrete path sampling is used to locate more kinetically relevant pathways
Summary
The influenza virus is a major cause of morbidity and mortality in humans. Viral infection is initiated by the binding of the trimeric hemagglutinin (HA) surface glycoprotein to glycans, which are terminated by the monosaccharide sialic acid, found on host cells in the upper respiratory tract. We have employed the computational tools of potential energy landscape theory, which exploits geometry optimization procedures to locate transition states and the minima they connect. For this complex conformational change, obtaining an initial connected path of minimum-transition stateminimum triples is itself a significant challenge. Our initial path contained around 4,500 steps, each one associated with a particular geometrical transition state (Murrell and Laidler, 1968), connecting a chain of local minima between the two selected pre- and post-fusion end points. Our focus in this report is on our initial mechanistic insights and how they were obtained
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