Multiconfigurational Coarse-Grained Molecular Dynamics

et al. 2022

Nat Commun

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The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

Section: Discussionmentioning

confidence: 99%

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

et al. 2022

Nat Commun

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“…In this work, we linearly mixed two model Hamiltonians that represent different configurational states (open and closed RBDs). Several additional approaches, including plastic network models (Maragakis & Karplus, 2005) and multi-configurational coarse-graining (Sharp, Vázquez, Wagner, Dannenhoffer-Lafage, & Voth, 2019), may prove useful to construct CG models capable of state transitions with increased accuracy for state populations and transition rates. These efforts will expand the capabilities of CG modeling, which in turn will provide valuable insight into collective molecular phenomena during SARS-CoV-2 infection, such as the role of cooperative multivalent ACE2 binding to induce spike trimer uncoating reported herein.…”

Section: Discussionmentioning

confidence: 99%

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

et al. 2021

Preprint

Self Cite

The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development and use of coarse-grained models and simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

“…24-25, 65, 67 Incorporating this structural transition into future CG models is likely to be non-trivial, but may be aided by recent methodological efforts to recapitulate conformational transitions within CG space. 68 Given that the presence of IP6 shifts mature CA assembly outcomes towards conical cores instead of tubules, 42 we speculate that mature CA assembles into tubules following a near-equilibrium pathway while the presence of IP6 induces kinetically-driven assembly into mature cores. Nonetheless, the present work highlights the utility and importance of kinetically-driven assembly in the context of immature HIV-1 viral particle production, although additional studies are needed to understand the connection between the fissure-like defects, the kinetics of PR activity throughout the immature lattice, and mature CA assembly during the final stages of maturation.…”

Section: Discussionmentioning

confidence: 91%

Inositol hexakisphosphate (IP6) accelerates immature HIV-1 Gag protein assembly towards kinetically-trapped morphologies

Gupta

Yeager

et al. 2022

Preprint

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During the late stages of the HIV-1 lifecycle, immature virions are produced by the concerted activity of Gag polyproteins, primarily mediated by the capsid (CA) and spacer peptide 1 (SP1) domains, which assemble into a spherical lattice, package viral genomic RNA, and deform the plasma membrane. Recently, inositol, hexakisphosphate (IP6) has been identified as an essential assembly cofactor that efficiently produces both immature virions in vivo and immature virus like particles in vitro. To date, however, several distinct mechanistic roles for IP6 have been proposed on the basis of independent functional, structural, and kinetic studies. In this work, we investigate the molecular influence of IP6 on the structural outcomes and dynamics of CA/SP1 assembly using coarse-grained (CG) molecular dynamics (MD) simulations and free energy calculations. Here, we derive a bottom-up, low-resolution, and implicit-solvent CG model of CA/SP1 and IP6, and simulate their assembly under conditions that emulate both in vitro and in vivo systems. Our analysis identifies IP6 as an assembly accelerant that promotes curvature generation and fissure-like defects throughout the lattice. Our findings suggest that IP6 induces kinetically-trapped immature morphologies, which may be physiologically important for later stages of viral morphogenesis and potentially useful for virus-like particle technologies.