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

TL;DR

This study uses molecular dynamics simulations to model SARS-CoV-2 assembly, focusing on RNA condensation, protein interactions, and membrane budding, revealing key mechanisms that could inform therapeutic strategies.

Contribution

It introduces a biophysical model of SARS-CoV-2 assembly, highlighting the roles of N and M proteins in genome packaging and virus budding, which are less studied compared to the S protein.

Findings

N proteins condense genomic RNA effectively.

M proteins' curvature is crucial for virus budding.

Insights into viral assembly mechanisms for drug targeting.

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 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.