Mechanisms of kinetic trapping in self-assembly and phase transformation

Hagan, Michael F.; Elrad, Oren M.; Jack, Robert L.

doi:10.1063/1.3635775

Cited by 111 publications

(164 citation statements)

References 58 publications

(135 reference statements)

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“…The rate at which emerging viruses develop or existing ones mutate requires urgent development of novel means to control their spread and ameliorate their effects (44,45). Viral capsid assembly is a central process in most cases, but is as yet a largely unexploited drug target (7,46,47). It has strong potential because malformed virus-like particles make good immunogens that expose conserved protein epitopes, or in the case of ssRNA plant viruses, the genomic RNA would trigger host gene silencing.…”

Section: Discussionmentioning

confidence: 99%

Solving a Levinthal's paradox for virus assembly identifies a unique antiviral strategy

Dykeman

Stockley

Twarock

2014

Proc. Natl. Acad. Sci. U.S.A.

110

123

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One of the important puzzles in virology is how viruses assemble the protein containers that package their genomes rapidly and efficiently in vivo while avoiding triggering their hosts' antiviral defenses. Viral assembly appears directed toward a relatively small subset of the vast number of all possible assembly intermediates and pathways, akin to Levinthal's paradox for the folding of polypeptide chains. Using an in silico assembly model, we demonstrate that this reduction in complexity can be understood if aspects of in vivo assembly, which have mostly been neglected in in vitro experimental and theoretical modeling assembly studies, are included in the analysis. In particular, we show that the increasing viral coat protein concentration that occurs in infected cells plays unexpected and vital roles in avoiding potential kinetic assembly traps, significantly reducing the number of assembly pathways and assembly initiation sites, and resulting in enhanced assembly efficiency and genome packaging specificity. Because capsid assembly is a vital determinant of the overall fitness of a virus in the infection process, these insights have important consequences for our understanding of how selection impacts on the evolution of viral quasispecies. These results moreover suggest strategies for optimizing the production of protein nanocontainers for drug delivery and of virus-like particles for vaccination. We demonstrate here in silico that drugs targeting the specific RNA-capsid protein contacts can delay assembly, reduce viral load, and lead to an increase of misencapsidation of cellular RNAs, hence opening up unique avenues for antiviral therapy.

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Section: Discussionmentioning

confidence: 99%

Solving a Levinthal's paradox for virus assembly identifies a unique antiviral strategy

Dykeman

Stockley

Twarock

2014

Proc. Natl. Acad. Sci. U.S.A.

110

123

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“…Most often, the main issue in equilibration-based (equilibrium) selfassembly lies in the tendency of colloidal mixtures to undergo dynamic arrest and form metastable disordered phases: precursors of the crystalline ground state [1][2][3] .…”

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confidence: 99%

Multistep kinetic self-assembly of DNA-coated colloids

et al. 2013

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Equilibrium self-assembly relies on the relaxation of disordered mixtures of building blocks towards an ordered ground state. The main drawback of this traditional approach lies in the kinetic traps that often interrupt the progression of the system towards equilibrium and lead to the formation of arrested phases. The latest techniques to control colloidal interactions open up the possibility of exploiting the tendency to dynamically arrest in order to construct amorphous materials with a specific morphology and local separation between multiple components. Here we propose strategies to direct the gelation of two-component colloidal mixtures by sequentially activating selective interactions. We investigate morphological changes in the structure of the arrested phases both by means of molecular dynamics simulations and experimentally by using DNA-coated colloids. Our approach can be exploited to assemble multicomponent mesoporous materials with possible applications in hybrid photovoltaics, photonics and drug delivery.

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“…While the number of possible graphs for a given model is exponential in the number of subunits N in the target structure, productive assembly reactions only visit a relatively small subset of possible structures. 73,140 Since the MSM state space includes only those states which are visited during estimation of the transition rate matrix, we expect only polynomial scaling. Although additional degrees of freedom, such as the number of subunits interacting with the scaffold (n s ), increases the size The number of unique transitions between states as a function of N. Both plots are from MSMs built using either (n s , n) or (n s , graphIso).…”

Section: Appendix D: Expected Scaling Of the Methods With Target Strucmentioning

confidence: 99%

“…This model has previously been used to study assembly around a polymer 72 and empty capsid assembly. 73 Similar models were applied to empty capsids by Rapaport 69-71 and Nguyen et al 63 More details are given in Appendix A 2.…”

Section: B Triangles Modelmentioning

confidence: 99%

Using Markov state models to study self-assembly

Perkett

Hagan

2014

The Journal of Chemical Physics

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Markov state models (MSMs) have been demonstrated to be a powerful method for computationally studying intramolecular processes such as protein folding and macromolecular conformational changes. In this article, we present a new approach to construct MSMs that is applicable to modeling a broad class of multi-molecular assembly reactions. Distinct structures formed during assembly are distinguished by their undirected graphs, which are defined by strong subunit interactions. Spatial inhomogeneities of free subunits are accounted for using a recently developed Gaussian-based signature. Simplifications to this state identification are also investigated. The feasibility of this approach is demonstrated on two different coarse-grained models for virus self-assembly. We find good agreement between the dynamics predicted by the MSMs and long, unbiased simulations, and that the MSMs can reduce overall simulation time by orders of magnitude. © 2014 AIP Publishing LLC.

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Mechanisms of kinetic trapping in self-assembly and phase transformation

Cited by 111 publications

References 58 publications

Solving a Levinthal's paradox for virus assembly identifies a unique antiviral strategy

Solving a Levinthal's paradox for virus assembly identifies a unique antiviral strategy

Multistep kinetic self-assembly of DNA-coated colloids

Using Markov state models to study self-assembly

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