This award is made on a RAPID proposal in response to the Coronavirus Disease 2019 Dear Colleague Letter. SARS-CoV-2 belongs to the family of coronaviruses and is responsible for the current pandemic. Untangling the steps and stages of how the components of the virus assemble themselves to make it is challenging. In contrast to icosahedral viruses which are shaped like a geodesic dome with 20 triangular sides, coronaviruses are heterogeneous both in size and morphology complicating their statistical reconstruction. While a fair amount of theory has been done for the assembly of icosahedral viruses, such an analysis has not been attempted for coronaviruses with their attendant complexities.
Since viruses have no independent energy source, assembly and budding strategies rely mainly on a combination of equilibrium statistical physics and the exploitation of active cellular processes hijacked for the formation of the virus. This project is focused on the investigating the assembly of SARS-CoV-2 both theoretically and through computer simulations.
Due to the lack of data necessary for the theory, this project also contains an experimental component. The project is focused on advancing understanding of the role of SARS-CoV2 structural proteins in its self-assembly using experiments. In particular, the PIs will use microscopy to study viral assembly within human cells and in vitro models, and to characterize particles collected from cells. The goal of experiments is to provide the basic necessary parameters for the theoretical investigation. By carrying out theory and experiment in concert, the PIs will obtain a deeper and more mechanistic understanding of the formation and assembly of SARS-CoV-2, which can contribute to the rapid design of effective drug therapies and thus will have a crucial role in combating the threat of the present and future global pandemic outbreaks of such coronaviruses.
The research supported through this award made on RAPID proposal will enable the development of coarse-grained simulations to study the role of several proteins involved in the formation of SARS-CoV-2 responsible for the Coronavirus Disease 2019 (COVID-19), which is spreading rapidly across the world, with tremendous adverse impact on health and the economy. Due to the urgency of the issue, numerous complementary strategies should be employed to tackle the problem and to improve the knowledge and information base.
SARS-CoV-2 forms at the membrane of the Endoplasmic Reticulum Golgi Intermediate Compartment (ERGIC). The assembly of SARS-CoV-2 is unique compared to many other viruses as both the assembly and budding occur simultaneously at the ERGIC membrane. Despite some investigation, very little is known of the assembly pathway or mechanism. This project is aimed to advance understanding of how SARS-CoV-2 assembles and provides a platform for other fundamental investigations to develop drugs and other strategies for treatment. A better understanding of physical principles involved in the formation of SARS-CoV-2 will advance the means of defeating the virus.
The research team will employ the methods of soft condensed matter and statistical mechanics of virus assembly, using both equilibrium and nonequilibrium approaches. Since virus assembly is akin to a thermodynamic phase transition, nucleation and growth theory will be used for the kinetics. Using the law of mass action and classical nucleation theory the PIs explore how the protein concentration, solution condition, that is, pH and salt concentration, influence the degree of assembly and budding. The analytical theory will be augmented by Monte Carlo simulations in grand canonical ensembles. This award also has an experimental component guided by the needs of the theory and simulation effort.
The particular intellectual merit of this proposal is the development of a dynamical theory of the coupled shape fluctuations of the membrane and the diffusion of proteins bound to it, and the testing of these results by the analysis of the experiments proposed.
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.