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

Lin, Xin; Noel, Jeffrey K.; Wang, Qinghua; Ma, Jianpeng; Onuchic, José N.

doi:10.1073/pnas.1805442115

Cited by 17 publications

(24 citation statements)

References 78 publications

(80 reference statements)

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“…to the extended helical intermediate is largely driven by trimerization of the A-helix and not the Bloop's loop-to-helix transition [103] Interestingly, in the soluble BHA ectodomain that lacks the transmembrane anchor, a direct, two-state transition from the pre-to post-fusion state was observed by HDX-MS. This striking result underscored the fact that in order to understand the mechanism of viral protein-mediated membrane fusion, it is necessary to examine how the conformational changes are carried out in the context of the complete viral system.…”

Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 97%

“…Consistent with this, computational studies also suggest that both the HA2 A-helix and B-loop segments can sample diverse structural states as they transition to the extended helical intermediate. Moreover, the computational modeling suggested that the transition to the extended helical intermediate is largely driven by trimerization of the A-helix and not the B-loop's loop-to-helix transition [103].…”

Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 99%

“…In this Viruses 2020, 12, 413 9 of 21 intermediate ensemble, the HA2 fusion peptide proximal subdomain features highly dynamic A-helix and B-loop segments (Figure 2B,C). The HA2 B-loop's loop-to-helix transition had long been viewed as the driving force behind formation of the HA2 extended helical intermediate and that, once freed from the HA1 "clamp", it was believed that the B-loop would rapidly and irreversibly adopt a helical conformation and add to the core HA2 helical bundle [21,30,103]. The HDX-MS data however, for the dynamic intermediate ensemble, revealed that the A-helix and B-loop sampled diverse secondary structure from unstructured loops to highly-protected helices [56].…”

Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 99%

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New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes

Benhaim

Lee

2020

Viruses

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Protein-mediated membrane fusion is a highly regulated biological process essential for cellular and organismal functions and infection by enveloped viruses. During viral entry the membrane fusion reaction is catalyzed by specialized protein machinery on the viral surface. These viral fusion proteins undergo a series of dramatic structural changes during membrane fusion where they engage, remodel, and ultimately fuse with the host membrane. The structural and dynamic nature of these conformational changes and their impact on the membranes have long-eluded characterization. Recent advances in structural and biophysical methodologies have enabled researchers to directly observe viral fusion proteins as they carry out their functions during membrane fusion. Here we review the structure and function of type I viral fusion proteins and mechanisms of protein-mediated membrane fusion. We highlight how recent technological advances and new biophysical approaches are providing unprecedented new insight into the membrane fusion reaction.Viruses 2020, 12, 413 2 of 21 built. Type II fusion proteins are found in viruses including flaviviruses and alphaviruses such as Dengue, Zika, and Chikungunya viruses, and even have been identified in eukaryotic cell-cell fusion systems [9][10][11][12]. Type III fusion proteins are found in rhabdoviruses (such as Rabies and Vesicular Stomatatis virus G glycoproteins), herpesviruses (Herpes Simplex virus 1 gB protein), as well as baculovirus [12][13][14][15][16]. While the individual folds exhibited by these classes are completely different, they share common functional traits in that all adopt a pre-fusion conformation prior to activation in which one terminus of the protein is anchored in the virus membrane by a transmembrane domain and a second membrane active component, either a fusion peptide or loop, is sequestered from interacting with membranes ( Figure 1) [12]. A trigger or set of triggers, such as exposure to low pH in endosomes or receptor binding, spurs the machinery to reorganize into a post-fusion state in which the two membrane active components are colocalized.Until recently, static structures of the pre-and post-fusion states of isolated fusion protein ectodomains and biochemical or spectroscopic measurements were the primary pieces of information that informed our models of membrane fusion. While the static structures provide defined endpoints for the conformational change that drives membrane fusion, they do not tell us how these conformational changes occur or how these proteins interact with and perturb the lipid membrane during fusion. Likewise, fluorescence spectroscopy and circular dichroism studies have shown that HA-fusion activation leads to population of discernable intermediates rather than transitioning directly and irreversibly from pre-to post-fusion states [17][18][19][20]. These studies show that not all HAs respond to activation in the same way and some require different pH conditions to fully activate [20]. While such studies provided valuable information...

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Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 97%

Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 99%

Section: Direct Monitoring Of the Transitions Between Conformational mentioning

confidence: 99%

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New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes

Benhaim

Lee

2020

Viruses

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“…Various mechanisms have been proposed for HA-mediated membrane fusion, based on equilibrium prefusion and postfusion crystal structures and biochemical evidence, but the details of this highly dynamic process are largely unknown. In PNAS, Lin et al (13) present important new insight into the energetic landscape and the dynamics of the pH-induced conformational changes that underlie HA-mediated membrane fusion based on all-atom molecular dynamics simulations of the full B-loop trimeric structure of HA 2 .…”

Section: Hemagglutinin As An Archetypementioning

confidence: 99%

“…While the mechanism of HA refolding has been difficult to characterize experimentally, molecular dynamics simulations offer a tractable approach to the problem. Lin et al (13) report all-atom, explicit-solvent molecular dynamics simulations to characterize the refolding of the trimeric B loop of the group 2 H3 HA. In the spring-loaded model, the B loop functions as a pH-dependent structural trigger that initiates and guides the initial HA refolding process.…”

Section: Molecular Dynamics Simulations Of Ha Refoldingmentioning

confidence: 99%