Energetics and Kinetic Assembly Pathways of Hepatitis B Virus Capsids in the Presence of Antivirals

Kra, Kalouna; Li, Siyu; Gargowitsch, Laetitia; Degrouard, Jéril; Pérez, Javier; Zandi, Roya; Bressanelli, Stéphane; Tresset, Guillaume

doi:10.1021/acsnano.3c03595

Cited by 10 publications

(3 citation statements)

References 54 publications

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“…The first possibility is that our simplified procedure does not capture some key property of bovine Norovirus VLP self-assembly. Apart from charge variation, the most obvious one is reversibility of subunit addition, an important feature of capsid self-assembly [57,58] that we do not consider when only adding VP1 dimers. But an alternate possibility is that the model of the intermediate proposed previously is not correct: So, pushing our reasoning, based on our new results, we propose that elongated intermediates composed of 10 dimers (Figure 6) may lock together to form a complete capsid.…”

Section: Discussionmentioning

confidence: 99%

Studying self-assembly of norovirus capsid by a combination ofin silicomethods

Carvaillo,

Tubiana,

Detchanamourtty

et al. 2024

Preprint

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Understanding how macromolecular assembly occurs is a fundamental and challenging problem because spontaneous, precise assembly is at the center of most biological processes. It is an elaborate process that requires non-covalent stable interactions between partners to stabilize the desired architecture for a specific purpose. One of the advantages of virus models is that under adequate conditions capsid proteins can be efficiently assembledin vitroin the absence of any other component, providing simplified experimental models that can be rigorously characterized. The present study aims at describing the initial steps of molecular self-assembly of norovirus-like particles (NoVLPs, composed solely of the major norovirus capsid protein VP1), by combiningin silicocomputational approaches to explore complementary physical properties. We show that this strategy allows not only recapitulating but also revising a former NoVLP assembly model. Our approach can be applied and extended to other problems in macromolecular assembly.

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Section: Discussionmentioning

confidence: 99%

Studying self-assembly of norovirus capsid by a combination ofin silicomethods

Carvaillo,

Tubiana,

Detchanamourtty

et al. 2024

Preprint

Self Cite

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“…More interestingly, by analyzing which transitions contribute most to the entropy production rate, one can identify factors that stabilize critical nuclei or other key intermediates, and whether these transitions lead to productive assembly or engender kinetic traps. These insights can form the basis for rational design of synthetic assembly systems, or, in the case of biomedically relevant assembly systems such as viruses, help to identify targets for antiviral molecules that interfere with assembly [213][214][215][216][217][218].…”

Section: Discussionmentioning

confidence: 99%

Optimization of non-equilibrium self-assembly protocols using Markov state models

Trubiano

Hagan

2022

The Journal of Chemical Physics

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The promise of self-assembly to enable bottom-up formation of materials with prescribed architectures and functions has driven intensive efforts to uncover rational design principles for maximizing the yield of a target structure. Yet, despite many successful examples of self-assembly, ensuring kinetic accessibility of the target structure remains an unsolved problem in many systems. In particular, long-lived kinetic traps can result in assembly times that vastly exceed experimentally accessible timescales. One proposed solution is to design non-equilibrium assembly protocols in which system parameters change over time to avoid such kinetic traps. Here, we develop a framework to combine Markov state model (MSM) analysis with optimal control theory to compute a time-dependent protocol that maximizes the yield of the target structure at a finite-time. We present an adjoint-based gradient descent method that, in conjunction with MSMs for a system as a function of its control parameters, enables efficiently optimizing the assembly protocol. We also describe an interpolation approach to significantly reduce the number of simulations required to construct the MSMs. We demonstrate our approach on two examples; a simple semi-analytic model for the folding of a polymer of colloidal particles, and a more complex model for capsid assembly. Our results show that optimizing time-dependent protocols can achieve significant improvements in yields of selected structures, including equilibrium free energy minima, long-lived metastable structures, and transient states.

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“…Mechanistically, CAMs appear to favor an assembly active state and stabilize dimer−dimer interactions. The net effect is that they accelerate assembly and encourage errors in the assembly process. − Of the many CAM families, heteroaryldihydropyrimidines (HAPs, Figures C and S1) are among the best characterized. In this work, we repurposed them as a chemical biology tool for cargo packaging and VLP decoration.…”

Section: Introductionmentioning

confidence: 99%

Chemically Tagging Cargo for Specific Packaging inside and on the Surface of Virus-like Particles

Hussain,

Zhao,

Murphy

et al. 2024

ACS Nano

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Virus-like particles (VLPs) have untapped potential for packaging and delivery of macromolecular cargo. To be a broadly useful platform, there needs to be a strategy for attaching macromolecules to the inside or the outside of the VLP with minimal modification of the platform or cargo. Here, we repurpose antiviral compounds that bind to hepatitis B virus (HBV) capsids to create a chemical tag to noncovalently attach cargo to the VLP. Our tag consists of a capsid assembly modulator, HAP13, connected to a linker terminating in maleimide. Our cargo is a green fluorescent protein (GFP) with a single addressable cysteine, a feature that can be engineered in many proteins. The HAP-GFP construct maintained HAP's intrinsic ability to bind HBV capsids and accelerate assembly. We investigated the capacity of HAP-GFP to coassemble with HBV capsid protein and bind to preassembled capsids. HAP-GFP binding was concentration-dependent, sensitive to capsid stability, and dependent on linker length. Long linkers had the greatest activity to bind capsids, while short linkers impeded assembly and damaged intact capsids. In coassembly reactions, >20 HAP-GFP molecules were presented on the outside and inside of the capsid, concentrating the cargo by more than 100-fold compared to bulk solution. We also tested an HAP-GFP with a cleavable linker so that external GFP molecules could be removed, resulting in exclusive internal packaging. These results demonstrate a generalizable strategy for attaching cargo to a VLP, supporting development of HBV as a modular VLP platform.

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Energetics and Kinetic Assembly Pathways of Hepatitis B Virus Capsids in the Presence of Antivirals

Cited by 10 publications

References 54 publications

Studying self-assembly of norovirus capsid by a combination ofin silicomethods

Studying self-assembly of norovirus capsid by a combination ofin silicomethods

Optimization of non-equilibrium self-assembly protocols using Markov state models

Chemically Tagging Cargo for Specific Packaging inside and on the Surface of Virus-like Particles

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