COMPUTATIONAL STUDIES OF CORONAVIRUSES SPIKE GLYCOPROTEIN CONFORMATIONAL PLASTICITY

The SARS-CoV-2 spike glycoprotein, a critical antigen recognized by antibodies, plays a key role in the viral life-cycle by binding to ACE2, promoting viral entry into host cells. Its prominence during the pandemic has led to the resolution of thousands of experimental spike structures. This protein is also the most mutated in viral variants, with these mutations affecting its structure, dynamics, and ligand affinity. This study aims to investigate the impact of spike protein interactions with various ligands and assess how mutations and their variants influence the structure of the SARS-CoV-2 spike protein and other coronaviruses. To assess the structural dynamics of SARS-CoV-2 spike proteins, we first created an ensemble using experimental spike structures from the PDB. Principal component analysis was employed to evaluate the ensemble's structural plasticity, while normal mode analysis predicted its intrinsic dynamics. Ensemble normal modes and dynamic network analyses were conducted to study spike movements. Molecular dynamics simulations with excited normal modes (MDeNM) were used for conformational free energy calculations. The primary movement of the SARS-CoV-2 spike involves the opening and closing of NTD and RBD, which accounts for approximately 90% of the protein's flexibility. This motion, predicted by the normal modes, is conserved across other coronaviruses, such as SARS-CoV-1 and MERS-CoV. Standard 10 μs molecular dynamics simulations did not capture the conformational change in the RBD. However, MDeNM enabled comprehensive exploration of the experimental ensemble conformational space, allowing accurate calculation of conformational free energy. Notably, the omicron variant exhibited distinct dynamics and interaction networks compared to other variants. These results highlight the efficacy of MDeNM in revealing detailed conformational dynamics and emphasize the distinct behaviors of viral variants, which may influence their biological functions and interactions. This work was supported by: Nasc. Des. Cient. Tecnológico (CNPq), Fund. Oswaldo Cruz (Fiocruz), Fund. Coord. Pessoa Nível Superior (CAPES), Fund. Carlos Chagas Filho Amp. Pesq. Estado Rio de Janeiro (FAPERJ) and Programa Inova Covid-19 (Geração de Conhecimento).