Physics of virus assembly and disassembly: Energetics and dynamics

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NONTECHNICAL SUMMARYThis award supports theoretical and computational research, and education to advance understanding of the factors contributing to the assembly and disassembly of virus particles. Viruses infect all kinds of hosts causing serious economic and health concerns worldwide. A critical step in the “life” cycle of most viruses, whether infecting bacteria, plants or animals, involves the formation of a protein shell, called the capsid that encloses the genome molecules (RNA or DNA). Viruses have not only optimized the feat of encapsulating their genetic material, but many of them have also evolved to efficiently disassemble and release their genetic materials upon entry into a host cell. Due to advances in experimental techniques at the nanoscale, the number of experiments investigating the physical basis of self-assembly and disassembly of viral particles is soaring. However, the current theoretical understanding of virus formation is incomplete. Improving this theory may guide the design of novel antiviral drugs based on direct interference of the virus assembly and/or disassembly. This award supports research aimed at making progress towards such a theory. In particular, the PI aims to develop theoretical and computational models for several new insightful experiments, which have raised basic questions relating to the formation and disassembly of virus particles. The models will describe how virus coat proteins assemble around their genetic material to form a stable shell and under what conditions a virus falls apart and release its genetic material. The results of the theoretical modeling and computer simulations will be assessed by testing model predictions against data from experiments. In advancing understanding of the formation and disassembly of viruses, this project contributes more generally to understanding the process of self-assembly which shapes much of the biomolecular world as well as biomaterials and polymer-based materials. This research on the assembly and disassembly of viruses is at the interface of condensed matter physics and biology and thus can have applications in other fields such as nanotechnology, drug delivery, and gene therapy. It can also play an important role in the development of alternative antiviral strategies based on direct interference of the capsid assembly and/or disassembly, which belong to the important areas for future studies. The research also contributes to the training of students interested in working on a new area of physical virology in a multidisciplinary field. The work of the PI will have an impact on the education of high school, undergraduate and graduate students, and in general to the training of the next generation of biological and soft condensed matter physicists.TECHNICAL SUMMARYThis award supports theoretical and computational research and education to advance understanding of the factors contributing to the assembly and disassembly of virus capsids. The current pandemic shows more than ever the urgency for learning about viruses at every level. A crucial step in the “life” cycle of most viruses, whether infecting bacteria, plants or animals, involves the formation of a protein shell, called the capsid that encloses the genome molecules (RNA or DNA). To fight viruses effectively, a comprehensive understanding of the critical steps and components of viral assembly or disassembly is essential in order to disrupt their formation. Despite a huge body of work dedicated to viruses, the knowledge about the formation of viruses and the means to combat them is still rudimentary.Several new insightful experiments have raised basic questions relating to the role of RNA in virus assembly and disassembly. The PI aims to address these questions by developing new theories and simulations. This project is aimed to address three major objectives: For objective one, the team will investigate several recent intriguing experiments corresponding to the assembly and disassembly of empty capsids built from some mutant capsid proteins. The goal of the second objective is to study the role of the genome in the kinetic pathways of virus assembly and disassembly and in defining the symmetry of viral shells with particular attention to several newly published and ongoing experiments. It appears that nucleic acid not only changes the size of the capsid but also has an impact on its symmetry. The effect of the genome on the kinetics pathways of assembly and disassembly of viral shells will also be investigated. The team will explore how it is possible for assembly or disassembly to occur spontaneously in one instance, and not in the other. Finally, disassembly also plays an important role in the formation of infectious human immunodeficiency viruses (HIV). For objective three, the team will explore how the disassembly of immature spherical HIV particles proceeds and is coupled to the formation of mature conical shells. The PI will extend the elasticity theory developed for spherical shells to explore the interactions between pentagonal defects as a spherical capsid grows, to conical and cylindrical shells. The goal is to decipher the factors that control the rate of transformation of a spherical shell to conical and cylindrical shells and find what physical considerations define the kinetics of this transformation.The fact that under many in vitro conditions single-stranded RNA viruses can spontaneously self-assemble by simply mixing their genome and capsid proteins, and by contrast, the change in pH or other thermodynamic parameters can result in the spontaneous disassembly of an otherwise stable virus, makes it possible to investigate the physical basis of virus assembly and disassembly in terms of the general principles of statistical mechanics and condensed matter physics. This project is aimed to extend modern methods of the statistical theory of soft matter such as elastic shells with topological defects, charged polymers of complex topologies, and supramolecular complexes to the emerging problems in physics of assembly and disassembly. This research on the assembly and disassembly of viruses is at the interface of condensed matter physics and biology and thus can have applications in other fields such as nanotechnology, drug delivery, and gene therapy. It can also play an important role in the development of alternative antiviral strategies based on direct interference of the capsid assembly and/or disassembly, which belong to the important areas for future studies. The research also contributes to the training of students interested in working on a new area of physical virology in a multidisciplinary field. The work of the PI will have an impact on the education of high school, undergraduate and graduate students, and in general to the training of the next generation of biological and soft condensed matter physicists.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.