tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2018 Jul 16. pii: 201805442. doi: 10.1073/pnas.1805442115. [Epub ahead of print]
[h=1]Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill.[/h] Lin X[SUP]1,[/SUP][SUP]2[/SUP], Noel JK[SUP]3[/SUP], Wang Q[SUP]4[/SUP], Ma J[SUP]1,[/SUP][SUP]4,[/SUP][SUP]5[/SUP], Onuchic JN[SUP]6,[/SUP][SUP]2,[/SUP][SUP]7,[/SUP][SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] B-loop transition; all-atom molecular dynamics; buried water; sequence divergence; structural heterogeneity
PMID: 30012616 DOI: 10.1073/pnas.1805442115
[h=1]Atomistic simulations indicate the functional loop-to-coiled-coil transition in influenza hemagglutinin is not downhill.[/h] Lin X[SUP]1,[/SUP][SUP]2[/SUP], Noel JK[SUP]3[/SUP], Wang Q[SUP]4[/SUP], Ma J[SUP]1,[/SUP][SUP]4,[/SUP][SUP]5[/SUP], Onuchic JN[SUP]6,[/SUP][SUP]2,[/SUP][SUP]7,[/SUP][SUP]8[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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.
[h=4]KEYWORDS:[/h] B-loop transition; all-atom molecular dynamics; buried water; sequence divergence; structural heterogeneity
PMID: 30012616 DOI: 10.1073/pnas.1805442115