Research

14 pages, 8955 KiB

Open AccessArticle

Molecular Dynamics Simulations of Deformable Viral Capsomers

by Lauren B. Nilsson, Fanbo Sun, J. C. S. Kadupitiya and Vikram Jadhao

Viruses 2023, 15(8), 1672; https://doi.org/10.3390/v15081672 - 31 Jul 2023

Viewed by 1050

Most coarse-grained models of individual capsomers associated with viruses employ rigid building blocks that do not exhibit shape adaptation during self-assembly. We develop a coarse-grained general model of viral capsomers that incorporates their stretching and bending energies while retaining many features of the [...] Read more.

Most coarse-grained models of individual capsomers associated with viruses employ rigid building blocks that do not exhibit shape adaptation during self-assembly. We develop a coarse-grained general model of viral capsomers that incorporates their stretching and bending energies while retaining many features of the rigid-body models, including an overall trapezoidal shape with attractive interaction sites embedded in the lateral walls to favor icosahedral capsid assembly. Molecular dynamics simulations of deformable capsomers reproduce the rich self-assembly behavior associated with a general

T = 1

icosahedral virus system in the absence of a genome. Transitions from non-assembled configurations to icosahedral capsids to kinetically-trapped malformed structures are observed as the steric attraction between capsomers is increased. An assembly diagram in the space of capsomer–capsomer steric attraction and capsomer deformability reveals that assembling capsomers of higher deformability into capsids requires increasingly large steric attraction between capsomers. Increasing capsomer deformability can reverse incorrect capsomer–capsomer binding, facilitating transitions from malformed structures to symmetric capsids; however, making capsomers too soft inhibits assembly and yields fluid-like structures. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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14 pages, 5595 KiB

Open AccessArticle

Fucose Binding Cancels out Mechanical Differences between Distinct Human Noroviruses

by Yuzhen Feng, Ronja Pogan, Lars Thiede, Jürgen Müller-Guhl, Charlotte Uetrecht and Wouter H. Roos

Viruses 2023, 15(7), 1482; https://doi.org/10.3390/v15071482 - 30 Jun 2023

Viewed by 1507

Abstract

The majority of nonbacterial gastroenteritis in humans and livestock is caused by noroviruses. Like most RNA viruses, frequent mutations result in various norovirus variants. The strain-dependent binding profiles of noroviruses to fucose are supposed to facilitate norovirus infection. It remains unclear, however, what [...] Read more.

The majority of nonbacterial gastroenteritis in humans and livestock is caused by noroviruses. Like most RNA viruses, frequent mutations result in various norovirus variants. The strain-dependent binding profiles of noroviruses to fucose are supposed to facilitate norovirus infection. It remains unclear, however, what the molecular mechanism behind strain-dependent functioning is. In this study, by applying atomic force microscopy (AFM) nanoindentation technology, we studied norovirus-like particles (noroVLPs) of three distinct human norovirus variants. We found differences in viral mechanical properties even between the norovirus variants from the same genogroup. The noroVLPs were then subjected to fucose treatment. Surprisingly, after fucose treatment, the previously found considerable differences in viral mechanical properties among these variants were diminished. We attribute a dynamic switch of the norovirus P domain upon fucose binding to the reduced differences in viral mechanical properties across the tested norovirus variants. These findings shed light on the mechanisms used by norovirus capsids to adapt to environmental changes and, possibly, increase cell infection. Hereby, a new step towards connecting viral mechanical properties to viral prevalence is taken. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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20 pages, 2696 KiB

Open AccessArticle

Novel Mode of nanoLuciferase Packaging in SARS-CoV-2 Virions and VLPs Provides Versatile Reporters for Virus Production

by Rebekah C. Gullberg and Judith Frydman

Viruses 2023, 15(6), 1335; https://doi.org/10.3390/v15061335 - 07 Jun 2023

Viewed by 2059

Abstract

SARS-CoV-2 is a positive-strand RNA virus in the Coronaviridae family that is responsible for morbidity and mortality worldwide. To better understand the molecular pathways leading to SARS-CoV-2 virus assembly, we examined a virus-like particle (VLP) system co-expressing all structural proteins together with an [...] Read more.

SARS-CoV-2 is a positive-strand RNA virus in the Coronaviridae family that is responsible for morbidity and mortality worldwide. To better understand the molecular pathways leading to SARS-CoV-2 virus assembly, we examined a virus-like particle (VLP) system co-expressing all structural proteins together with an mRNA reporter encoding nanoLuciferase (herein nLuc). Surprisingly, the 19 kDa nLuc protein itself was encapsidated into VLPs, providing a better reporter than nLuc mRNA itself. Strikingly, infecting nLuc-expressing cells with the SARS-CoV-2, NL63 or OC43 coronaviruses yielded virions containing packaged nLuc that served to report viral production. In contrast, infection with the flaviviruses, dengue or Zika, did not lead to nLuc packaging and secretion. A panel of reporter protein variants revealed that the packaging is size-limited and requires cytoplasmic expression, indicating that the large virion of coronaviruses can encaspidate a small cytoplasmic reporter protein. Our findings open the way for powerful new approaches to measure coronavirus particle production, egress and viral entry mechanisms. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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15 pages, 3337 KiB

Open AccessArticle

Construction of a Chikungunya Virus, Replicon, and Helper Plasmids for Transfection of Mammalian Cells

by Mayra Colunga-Saucedo, Edson I. Rubio-Hernandez, Miguel A. Coronado-Ipiña, Sergio Rosales-Mendoza, Claudia G. Castillo and Mauricio Comas-Garcia

Viruses 2023, 15(1), 132; https://doi.org/10.3390/v15010132 - 31 Dec 2022

Cited by 2 | Viewed by 2166

Abstract

The genome of Alphaviruses can be modified to produce self-replicating RNAs and virus-like particles, which are useful virological tools. In this work, we generated three plasmids for the transfection of mammalian cells: an infectious clone of Chikungunya virus (CHIKV), one that codes for [...] Read more.

The genome of Alphaviruses can be modified to produce self-replicating RNAs and virus-like particles, which are useful virological tools. In this work, we generated three plasmids for the transfection of mammalian cells: an infectious clone of Chikungunya virus (CHIKV), one that codes for the structural proteins (helper plasmid), and another one that codes nonstructural proteins (replicon plasmid). All of these plasmids contain a reporter gene (mKate2). The reporter gene in the replicon RNA and the infectious clone are synthesized from subgenomic RNA. Co-transfection with the helper and replicon plasmids has biotechnological/biomedical applications because they allow for the delivery of self-replicating RNA for the transient expression of one or more genes to the target cells. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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20 pages, 7003 KiB

Open AccessEditor’s ChoiceArticle

Biophysical Modeling of SARS-CoV-2 Assembly: Genome Condensation and Budding

by Siyu Li and Roya Zandi

Viruses 2022, 14(10), 2089; https://doi.org/10.3390/v14102089 - 20 Sep 2022

Cited by 9 | Viewed by 6896

Abstract

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred unprecedented and concerted worldwide research to curtail and eradicate this pathogen. SARS-CoV-2 has four structural proteins: Envelope (E), Membrane (M), Nucleocapsid (N), and Spike (S), which self-assemble along [...] Read more.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spurred unprecedented and concerted worldwide research to curtail and eradicate this pathogen. SARS-CoV-2 has four structural proteins: Envelope (E), Membrane (M), Nucleocapsid (N), and Spike (S), which self-assemble along with its RNA into the infectious virus by budding from intracellular lipid membranes. In this paper, we develop a model to explore the mechanisms of RNA condensation by structural proteins, protein oligomerization and cellular membrane–protein interactions that control the budding process and the ultimate virus structure. Using molecular dynamics simulations, we have deciphered how the positively charged N proteins interact and condense the very long genomic RNA resulting in its packaging by a lipid envelope decorated with structural proteins inside a host cell. Furthermore, considering the length of RNA and the size of the virus, we find that the intrinsic curvature of M proteins is essential for virus budding. While most current research has focused on the S protein, which is responsible for viral entry, and it has been motivated by the need to develop efficacious vaccines, the development of resistance through mutations in this crucial protein makes it essential to elucidate the details of the viral life cycle to identify other drug targets for future therapy. Our simulations will provide insight into the viral life cycle through the assembly of viral particles de novo and potentially identify therapeutic targets for future drug development. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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Review

Jump to: Research, Other

34 pages, 10236 KiB

Open AccessReview

Analyzing the Geometry and Dynamics of Viral Structures: A Review of Computational Approaches Based on Alpha Shape Theory, Normal Mode Analysis, and Poisson–Boltzmann Theories

by Yin-Chen Hsieh, Marc Delarue, Henri Orland and Patrice Koehl

Viruses 2023, 15(6), 1366; https://doi.org/10.3390/v15061366 - 13 Jun 2023

Cited by 1 | Viewed by 1928

Abstract

The current SARS-CoV-2 pandemic highlights our fragility when we are exposed to emergent viruses either directly or through zoonotic diseases. Fortunately, our knowledge of the biology of those viruses is improving. In particular, we have more and more structural information on virions, i.e., [...] Read more.

The current SARS-CoV-2 pandemic highlights our fragility when we are exposed to emergent viruses either directly or through zoonotic diseases. Fortunately, our knowledge of the biology of those viruses is improving. In particular, we have more and more structural information on virions, i.e., the infective form of a virus that includes its genomic material and surrounding protective capsid, and on their gene products. It is important to have methods that enable the analyses of structural information on such large macromolecular systems. We review some of those methods in this paper. We focus on understanding the geometry of virions and viral structural proteins, their dynamics, and their energetics, with the ambition that this understanding can help design antiviral agents. We discuss those methods in light of the specificities of those structures, mainly that they are huge. We focus on three of our own methods based on the alpha shape theory for computing geometry, normal mode analyses to study dynamics, and modified Poisson–Boltzmann theories to study the organization of ions and co-solvent and solvent molecules around biomacromolecules. The corresponding software has computing times that are compatible with the use of regular desktop computers. We show examples of their applications on some outer shells and structural proteins of the West Nile Virus. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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23 pages, 20381 KiB

Open AccessReview

Viral Aggregation: The Knowns and Unknowns

by Swechchha Pradhan, Arvind Varsani, Chloe Leff, Carter J. Swanson and Rizal F. Hariadi

Viruses 2022, 14(2), 438; https://doi.org/10.3390/v14020438 - 21 Feb 2022

Cited by 18 | Viewed by 5911

Abstract

Viral aggregation is a complex and pervasive phenomenon affecting many viral families. An increasing number of studies have indicated that it can modulate critical parameters surrounding viral infections, and yet its role in viral infectivity, pathogenesis, and evolution is just beginning to be [...] Read more.

Viral aggregation is a complex and pervasive phenomenon affecting many viral families. An increasing number of studies have indicated that it can modulate critical parameters surrounding viral infections, and yet its role in viral infectivity, pathogenesis, and evolution is just beginning to be appreciated. Aggregation likely promotes viral infection by increasing the cellular multiplicity of infection (MOI), which can help overcome stochastic failures of viral infection and genetic defects and subsequently modulate their fitness, virulence, and host responses. Conversely, aggregation can limit the dispersal of viral particles and hinder the early stages of establishing a successful infection. The cost–benefit of viral aggregation seems to vary not only depending on the viral species and aggregating factors but also on the spatiotemporal context of the viral life cycle. Here, we review the knowns of viral aggregation by focusing on studies with direct observations of viral aggregation and mechanistic studies of the aggregation process. Next, we chart the unknowns and discuss the biological implications of viral aggregation in their infection cycle. We conclude with a perspective on harnessing the therapeutic potential of this phenomenon and highlight several challenging questions that warrant further research for this field to advance. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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Other

Jump to: Research, Review

12 pages, 1236 KiB

Open AccessHypothesis

Relevance of Host Cell Surface Glycan Structure for Cell Specificity of Influenza A Viruses

by Markus Kastner, Andreas Karner, Rong Zhu, Qiang Huang, Andreas Geissner, Anne Sadewasser, Markus Lesch, Xenia Wörmann, Alexander Karlas, Peter H. Seeberger, Thorsten Wolff, Peter Hinterdorfer, Andreas Herrmann and Christian Sieben

Viruses 2023, 15(7), 1507; https://doi.org/10.3390/v15071507 - 05 Jul 2023

Viewed by 1307

Abstract

Influenza A viruses (IAVs) initiate infection via binding of the viral hemagglutinin (HA) to sialylated glycans on host cells. HA’s receptor specificity towards individual glycans is well studied and clearly critical for virus infection, but the contribution of the highly heterogeneous and complex [...] Read more.

Influenza A viruses (IAVs) initiate infection via binding of the viral hemagglutinin (HA) to sialylated glycans on host cells. HA’s receptor specificity towards individual glycans is well studied and clearly critical for virus infection, but the contribution of the highly heterogeneous and complex glycocalyx to virus–cell adhesion remains elusive. Here, we use two complementary methods, glycan arrays and single-virus force spectroscopy (SVFS), to compare influenza virus receptor specificity with virus binding to live cells. Unexpectedly, we found that HA’s receptor binding preference does not necessarily reflect virus–cell specificity. We propose SVFS as a tool to elucidate the cell binding preference of IAVs, thereby including the complex environment of sialylated receptors within the plasma membrane of living cells. Full article

(This article belongs to the Special Issue Physical Virology - Viruses at Multiple Levels of Complexity)

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