MOLECULAR INTERACTIONS OF SARS-COV-2 MEMBRANE PEPTIDES VIA MOLECULAR DYNAMICS SIMULATIONS

Identified in December 2019, SARS-CoV-2, an enveloped virus, was responsible for the global COVID-19 pandemic. This virus enters host cells by fusing its viral membrane with the cellular one, a process mediated by the Spike protein, particularly by two regions called the fusion peptide (FP) and the transmembrane domain (TM). A recent cryo-electron microscopy study performed in lipid nanodiscs suggests that FP and TM interact with each other, forming 9-helix bundle. However, the mechanisms underlying this structure and how the FP acquires a transmembrane topology are still poorly understood. This study employs molecular dynamics (MD) simulations using the NAMD software to analyze the molecular interactions of these two viral membrane peptide segments, aiming to investigate the stability of the post-fusion peptide conformations and the mechanism of complex formation. A total of 1.5 μs MD simulations was performed, and the data were analyzed in terms of root mean square deviation (RMSD) and the measurement of the peptide’s center of mass position relative to the lipid bilayer center. Preliminary results indicate that the transmembrane topology and the secondary structure of the TM domain are stable throughout the simulations. On the other hand, the fusion peptide alone does not seem to adopt a transmembrane conformation but remains bonded to the bilayer at all times. Additionally, FP displays higher conformational flexibility compared to TM in all systems investigated. The data suggest that FP requires homo-oligomerization (interaction with other FPs) or hetero-oligomerization (interaction with TM) to achieve a transmembrane topology. We are currently working on further investigation and interpretation of the obtained data and on extending the current simulations for a better understanding of the interaction between FP and TM with the membranes, their dynamics in the lipid bilayers, and the stability of the post-fusion state of the Spike protein.

This work was supported by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ processes 210.778/2021 and 211.816/2021), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).