Research Projects

Membrane fusion is a critical step in the life cycle of enveloped viruses like SARS-CoV-2, enabling the viral genome to enter host cells. In SARS-CoV-2, this process is mediated by the spike protein, which includes a receptor-binding S1 domain and a fusion-mediating S2 domain, separated by a unique S2 furin cleavage site. S1 binds to the ACE2 receptor, triggering conformational changes that activate the transition in S2 domain. Notably, S2 contains a second cleavage site, S2′, conserved across coronaviruses, which is essential for completing the fusion. While structures of the prefusion and postfusion spike have been resolved, the intermediate steps and transition mechanisms remain poorly understood. These intermediates are critical to infection and represent promising but underexplored antiviral targets. There are several key questions that remains unexplored. What thermodynamic interactions stabilize the S1/S2 complex in the prefusion state? Why is the conserved S2′ cleavage more essential than the unique S2 furin cleavage? What is the role of the S2-S2′ linker during the conformational transition? And what are the intermediate events that govern membrane fusion? These questions are difficult to address experimentally due to the transient nature of intermediates and limited resolution. Molecular dynamics (MD) simulations can capture the transient events, but it is limited by system size and timescales, especially for large complexes like the spike protein and the long-time scale membrane fusion processes. To address these challenges, we propose a multiscale modeling approach using structure-based models (SBMs). SBMs are native-biased models capable of capturing large protein conformational changes and have been applied successfully to study protein folding and transitions. We will extend this framework to model the spike’s transition from prefusion to postfusion, with emphasis on the S1/S2 interface and S2-S2′ linker. These simulations will offer mechanistic insight into the spike transition pathway and inform inhibitor design targeting S2′ cleavage or S2 domain activation. Additionally, we will develop a hybrid model by combining the SBM multi-basin strategy with the MARTINI force field to simulate membrane fusion with a realistic lipid composition. While SBMs simplify membrane representation, MARTINI accurately models lipid bilayers and protein-membrane interactions but lacks capacity for large-scale conformational transitions. Our hybrid model will bridge these gaps to capture spike-driven fusion events and key intermediates. This work will provide fundamental insights into SARS-CoV-2 membrane fusion and establish a transferable modeling framework for other enveloped viruses such as influenza, HIV, and hepatitis C. The developed tools can aid in therapeutic discovery targeting viral entry mechanisms.