Virus self-assembly proceeds through contact-rich energy minima

Buzón, Pedro; Maity, Sourav; Christodoulis, Panagiotis; Wiertsema, Monique J.; Dunkelbarger, Steven; Kim, Christine; Wuite, Gijs J. L.; Zlotnick, Adam; Roos, Wouter H.

doi:10.1126/sciadv.abg0811

Cited by 28 publications

(22 citation statements)

References 76 publications

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“…Trajectories that form such an intermediate will go on to form either T =4 capsids or malformed structures, whereas trajectories that diverge from the T =4 pathway before forming a complete T =4 dodecamer form either T =3 capsids or malformed structures. This prediction is consistent with recent AFM observations of HBV capsid protein assembly [33]. Knowledge of hub states could suggest new antiviral drug targets.…”

Section: Discussionsupporting

confidence: 92%

“…The T =4 dodecamer was identified as a frequently observed intermediate along T =4 assembly pathways in AFM measurements of HBV dimers assembling on a mica plate [33]. The significance of this structure to formation of T =4 capsids in our simulations qualitatively agrees with this observation.…”

Section: Resultssupporting

confidence: 84%

“…Each simulation begins with an initial state comprising three edges in a triangular face. This state is known to be a highly populated intermediate, and is estimated to be the critical nucleus for HBV capsid assembly [33, 119, 137]. Each simulation contains a single assembly, which undergoes exchange of subunits with a reservoir according to the grand canonical probability density, Eq.…”

Section: Supporting Informationmentioning

confidence: 99%

“…Recently, Cp149 assembly size distributions have been measured near or at single-subunit precision using resistive pulse sensing [26, 27], mass spectrometry [28], and charge detection mass spectrometry [29–32], and small intermediates were identified by highspeed AFM [33]. These experiments identified a number of long-lived intermediate structures with sizes between 85-140 dimers.…”

Section: Introductionmentioning

confidence: 99%

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Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism

Mohajerani

Tyukodi

Schlicksup

et al. 2022

Preprint

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Hepatitis B Virus (HBV) is an endemic, chronic virus that leads to 800,000 deaths per year. Central to the HBV lifecycle, the viral core has a protein capsid assembled from many copies of a single protein. The capsid protein adopts different (quasi-equivalent) conformations to form icosahedral capsids containing 180 or 240 proteins, T=3 or T=4 respectively in Caspar-Klug nomenclature. HBV capsid assembly has become an important target for new antivirals; nonetheless the assembly pathways and mechanisms that control HBV dimorphism remain unclear. We describe computer simulations of HBV assembly, using a coarse-grained model that has parameters learned from all-atom molecular dynamics simulations of a complete HBV capsid, and yet is computationally tractable. Dynamical simulations with the resulting model reproduce experimental observations of HBV assembly pathways and products. By constructing Markov state models and employing transition path theory, we identify pathways leading to T=3, T=4, and other experimentally observed capsid morphologies. The analysis identifies factors that control this polymorphism, in particular, the conformational free energy landscape of the capsid proteins and their interactions.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 84%

Section: Supporting Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism

Mohajerani

Tyukodi

Schlicksup

et al. 2022

Preprint

Self Cite

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“…Resolving the empty capsid assembly mechanism is already a very challenging problem, [24][25][26][27][28][29][30][31][32][33] despite recent progress with experimental techniques such as resistive pulse sensing , 34,35 mass spectrometry, 36 charge detection mass spectrometry, [37][38][39][40] and solution small-angle Xray scattering (SAXS). [41][42][43][44][45][46][47] Our lab, however, developed a robust and transparent mechanism for isolating the most probable intermediates at equilibrium and on the assembly path of an empty Hepatitis B capsid. 48 Using MC simulations, we created a library of representative intermediates and showed that at equilibrium a very limited number of relevant assembly reaction products were selected based on their Boltzmann weights, computed from the self-association standard free energy between subunits.…”

Section: Introductionmentioning

confidence: 99%

Effect of Ionic Strength on the Assembly of Simian Vacuolating Virus Capsid Protein Around Poly(Styrene Sulfonate)

Asor

Singaram

Levi‐Kalisman

et al. 2022

Preprint

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Virus-like particles (VLPs) are noninfectious nanocapsules that can be used for drug delivery or vaccine applications. VLPs can be assembled from virus capsid proteins around a condensing agent like RNA, DNA, or a charged polymer. Electrostatic interactions play an important role in the assembly reaction. VLPs assemble from many copies of capsid protein, with combinatorial intermediates, and therefore the mechanism of the reaction is poorly understood. In this paper, we determined the effect of ionic strength on the assembly of Simian Vacuolating Virus 40 (SV40)-like particles. We mixed poly(styrene sulfonate) with SV40 capsid protein pentamers at different ionic strengths. We then characterized the assembly product by solution small-angle X-ray scattering (SAXS) and cryo-TEM. To analyze the data, we performed Brownian dynamics simulations using a coarse-grained model that revealed incomplete, asymmetric VLP structures that were consistent with the experimental data. We found that close to physiological ionic strength, T=1 VLPs coexisted with VP1 pentamers. At lower or higher ionic strengths, incomplete particles coexisted with pentamers and T=1 particles. Including the simulation, structures were essential to explaining the SAXS data.

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The Histone Chaperones SET/TAF‐1β and NPM1 Exhibit Conserved Functionality in Nucleosome Remodeling and Histone Eviction in a Cytochrome c‐Dependent Manner

et al. 2023

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Chromatin homeostasis mediates essential processes in eukaryotes, where histone chaperones have emerged as major regulatory factors during DNA replication, repair, and transcription. The dynamic nature of these processes, however, has severely impeded their characterization at the molecular level. Here, fluorescence optical tweezers are applied to follow histone chaperone dynamics in real time. The molecular action of SET/template‐activating factor‐Iβ and nucleophosmin 1—representing the two most common histone chaperone folds—are examined using both nucleosomes and isolated histones. It is shown that these chaperones present binding specificity for fully dismantled nucleosomes and are able to recognize and disrupt non‐native histone‐DNA interactions. Furthermore, the histone eviction process and its modulation by cytochrome c are scrutinized. This approach shows that despite the different structures of these chaperones, they present conserved modes of action mediating nucleosome remodeling.

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Virus self-assembly proceeds through contact-rich energy minima

Abstract: Single-molecule fluorescence optical tweezers studies combined with high-speed AFM reveal early events in the HBV life cycle.

Cited by 28 publications

References 76 publications

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism

Multiscale Modeling of Hepatitis B Virus Capsid Assembly and its Dimorphism

Effect of Ionic Strength on the Assembly of Simian Vacuolating Virus Capsid Protein Around Poly(Styrene Sulfonate)

The Histone Chaperones SET/TAF‐1β and NPM1 Exhibit Conserved Functionality in Nucleosome Remodeling and Histone Eviction in a Cytochrome c‐Dependent Manner

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