Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill

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Title:	Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill
Creators Name:	Lin, X., Noel, J.K., Wang, Q., Ma, J. and Onuchic, J.N.
Abstract:	Influenza hemagglutinin (HA) mediates viral entry into host cells through a large-scale conformational rearrangement at low pH that leads to fusion of the viral and endosomal membranes. Crystallographic and biochemical data suggest that a loop-to-coiled-coil transition of the B-loop region of HA is important for driving this structural rearrangement. However, the microscopic picture for this proposed "spring-loaded" movement is missing. In this study, we focus on understanding the transition of the B loop and perform a set of all-atom molecular dynamics simulations of the full B-loop trimeric structure with the CHARMM36 force field. The free-energy profile constructed from our simulations describes a B loop that stably folds half of the postfusion coiled coil in tens of microseconds, but the full coiled coil is unfavorable. A buried hydrophilic residue, Thr59, is implicated in destabilizing the coiled coil. Interestingly, this conserved threonine is the only residue in the B loop that strictly differentiates between the group 1 and 2 HA molecules. Microsecond-scale constant temperature simulations revealed that kinetic traps in the structural switch of the B loop can be caused by nonnative, intramonomer, or intermonomer β-sheets. The addition of the A helix stabilized the postfusion state of the B loop, but introduced the possibility for further β-sheet structures. Overall, our results do not support a description of the B loop in group 2 HAs as a stiff spring, but, rather, it allows for more structural heterogeneity in the placement of the fusion peptides during the fusion process.
Keywords:	All-Atom Molecular Dynamics, B-Loop Transition, Structural Heterogeneity, Buried Water, Sequence Divergence
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	115
Number:	34
Page Range:	E7905-E7913
Date:	21 August 2018
Official Publication:	https://doi.org/10.1073/pnas.1805442115
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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