“Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly”

Grime, John M. A.; Dama, James F.; Ganser‐Pornillos, Barbie K.; Woodward, Cora L.; Jensen, Grant J.; Yeager, Mark; Voth, Gregory A.

doi:10.1101/040741

Cited by 47 publications

(91 citation statements)

References 67 publications

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“…This behavior is indicative of kinetic trapping, known to occur in assembly reactions at high concentrations or binding affinities (73,74). The ability of an inactive conformation to avoid this trap is consistent with simulations of bulk assembly (59,60), and the ability of budding to proceed in the presence of high subunit concentrations (when conformational changes are accounted for), which is consistent with the observation of high densities of GPs in the membranes of cells infected with Sindbis virus (75).…”

Section: Gp Conformational Changes Avoid Kinetic Trapssupporting

confidence: 84%

“…Experiments on several viral families suggest that viral proteins interconvert between ''assembly active'' and ''assembly inactive'' conformations, which are respectively compatible or incompatible with assembly into the virion (56)(57)(58). Computational models suggest that such conformational dynamics can suppress kinetic traps (59,60). Conformational changes of the alphavirus GPs E1 and E2 are required for dimerization in the cytoplasm, and it has been proposed that the GPs interconvert between assembly inactive and assembly active conformations (58), possibly triggered by interaction with NC proteins (18).…”

Section: Subunit Conformational Changesmentioning

confidence: 99%

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Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Lázaro

Mukhopadhyay

Hagan

2018

Biophysical Journal

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During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid. We find that there is a transition between glycoprotein-directed budding and nucleocapsid-directed budding that occurs above a threshold strength of nucleocapsid interactions. The simulations predict that glycoprotein-directed budding leads to significantly increased size polydispersity and particle polymorphism. This polydispersity can be explained by a theoretical model accounting for the competition between bending energy of the membrane and the glycoprotein shell. The simulations also show that the geometry of a budding particle leads to a barrier to subunit diffusion, which can result in a stalled, partially budded state. We present a phase diagram for this and other morphologies of budded particles. Comparison of these structures against experiments could establish bounds on whether budding is directed by glycoprotein or nucleocapsid interactions. Although our model is motivated by alphaviruses, we discuss implications of our results for other enveloped viruses.

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Section: Gp Conformational Changes Avoid Kinetic Trapssupporting

confidence: 84%

Section: Subunit Conformational Changesmentioning

confidence: 99%

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Lázaro

Mukhopadhyay

Hagan

2018

Biophysical Journal

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“…However, in the latter case assembly typically requires relatively high protein concentrations and very high ionic strength (51,52,54) that may screen electrostatic repulsions in CA (63)(64)(65), a macromolecular crowding agent (53,66), or use of fused NC protein and added nucleic acid (67). In contrast, fast and efficient self-assembly of the CA lattice as a nanocoating on mica takes place even at CA concentrations <1 mM at close to physiological ionic strength and pH in the absence of crowding agents, NC and RNA.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Surface-Driven Self-Assembly and Fatigue-Induced Disassembly of a Virus-Based Nanocoating

Valbuena

Mateu

2017

Biophysical Journal

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Self-assembling protein layers provide a ''bottom-up'' approach for precisely organizing functional elements at the nanoscale over a large solid surface area. The design of protein sheets with architecture and physical properties suitable for nanotechnological applications may be greatly facilitated by a thorough understanding of the principles that underlie their self-assembly and disassembly. In a previous study, the hexagonal lattice formed by the capsid protein (CA) of human immunodeficiency virus (HIV) was self-assembled as a monomolecular layer directly onto a solid substrate, and its mechanical properties and dynamics at equilibrium were analyzed by atomic force microscopy. Here, we use atomic force microscopy to analyze the kinetics of self-assembly of the planar CA lattice on a substrate and of its disassembly, either spontaneous or induced by materials fatigue. Both selfassembly and disassembly of the CA layer are cooperative reactions that proceed until a phase equilibrium is reached. Self-assembly requires a critical protein concentration and is initiated by formation of nucleation points on the substrate, followed by lattice growth and eventual merging of CA patches into a continuous monolayer. Disassembly of the CA layer showed hysteresis and appears to proceed only after large enough defects (nucleation points) are formed in the lattice, whose number is largely increased by inducing materials fatigue that depends on mechanical load and its frequency. Implications of the kinetic results obtained for a better understanding of self-assembly and disassembly of the HIV capsid and protein-based two-dimensional nanomaterials and the design of anti-HIV drugs targeting (dis)assembly and biocompatible nanocoatings are discussed.

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“…The length and time-scales of such dynamics are difficult or impossible with the alternative and standard computational approach for self-assembly of coarse-grained molecular dynamics (MD)type models [9][10][11] . For those models, interactions emerge due to distance-dependent energy functions rather than rate-controlled events, so while they are more physically realistic, they lack systematic and transferable methods for involving enzymatic or ATP-driven reactions ubiquitous in cells.…”

Section: Introductionmentioning

confidence: 99%

NERDSS: a non-equilibrium simulator for multibody self-assembly at the cellular scale

Varga

Loggia

et al. 2019

Preprint

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Currently, a significant barrier to building predictive models of cell-based self-assembly processes is that molecular models cannot capture minutes-long cellular dynamics that couple distinct components with active processes, while reaction-diffusion models lack sufficient detail for capturing assembly structures. Here we introduce the Non-Equilibrium Reaction-Diffusion Selfassembly Simulator (NERDSS), which addresses this gap by integrating a structure-resolved reaction-diffusion algorithm with rule-based model construction. By representing proteins as rigid, multi-site molecules that adopt well-defined orientations upon binding, NERDSS simulates formation of large reversible structures with sites that can be acted on by reaction rules. We show how NERDSS allows for directly comparing and optimizing models of multi-component assembly against time-dependent experimental data. Applying NERDSS to assembly steps in clathrin-mediated endocytosis, we capture how the formation of clathrin caged structures can be driven by modulating the strength of clathrin-clathrin interactions, by adding cooperativity, or by localizing clathrin to the membrane. NERDSS further predicts how clathrin lattice disassembly can be driven by enzymes that irreversibly change lipid populations on the membrane. By modeling viral lattice assembly and recapitulating oscillations in protein expression levels for a circadian clock model, we illustrate the wide usability and adaptability of NERDSS. NERDSS simulates user-defined assembly models that were previously inaccessible to existing software tools, with broad applications to predicting self-assembly in vivo and designing high-yield assemblies in vitro.

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“Coarse-grained simulation reveals key features of HIV-1 capsid self-assembly”

Cited by 47 publications

References 67 publications

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Kinetics of Surface-Driven Self-Assembly and Fatigue-Induced Disassembly of a Virus-Based Nanocoating

NERDSS: a non-equilibrium simulator for multibody self-assembly at the cellular scale

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