期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 34, 页码 E7905-E7913出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1805442115
关键词
all-atom molecular dynamics; B-loop transition; structural heterogeneity; buried water; sequence divergence
资金
- Center for Theoretical Biological Physics - NSF [PHY-1427654]
- NSF Division of Chemistry Grant [1614101]
- Welch Foundation [C-1792, Q-1512, Q-1826]
- National Institute of Health [R01-GM110310, R01-GM067801, R01-GM116280, R01-GM127628, R01-AI067839]
- National Science Foundation [MCB-0818353, ACI-1548562]
- Pittsburgh Supercomputing Center (PSC) through National Institutes of Health [PSCA14037P, R01-GM116961]
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-tocoiled-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 beta-sheets. The addition of the A helix stabilized the postfusion state of the B loop, but introduced the possibility for further beta-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.
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