Dimerization mechanism and associated solvation effects in non-structural protein 9 (NSP9) of coronavirus

• Grant number: 23/13899-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2023
• End date: October 31, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Physical-Chemistry
• Principal Investigator: Leandro Martinez
• Grantee: Jéssica de Oliveira Araújo
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/08293-7 - CCES - Center for Computational Engineering and Sciences, AP.CEPID

Abstract

In this research project we will study the effect of solvation on protein-protein association, using as an example the formation of the non-structural protein 9 dimer (NSP9) of SARS-CoV-2. NSP9 has been considered important for virus replication while human cells are being infected. It has been observed that this dimerization in solution occurs through a preserved ±-helicoidal motif called "GxxxG." The change in key residues within this motif reduces RNA binding and viral proliferation. The preserved pattern of protein-protein interaction provides van der Waals interactions between the glycine residues on the interface that make up the C-terminal ±-helix. Molecular dynamics simulations provide a way to study processes such as the dissociation or association of these proteins, where it is possible to study the formation of interactions that stabilize the dimer by producing detailed structural and thermodynamic data. The main objective of the project is to provide information on the structural transformation undergone by the protein upon dissociation of dimers and to study how solvents, whether pure water or in the presence of ions or other cosolvents, act in this process. The research will be carried out using methods of steered molecular dynamics (SMD) combined with umbrella sampling (US) techniques in aqueous solutions with different solvents of biochemical relevance. Thus, it will involve the structural study of how these monomers behave, in addition to the energy profile associated with this process, their solvation, and a detailed study of solute-solvent interactions and thermodynamics. Solvation structures will be studied using minimum-distance distribution functions, using the group's expertise, by means of the ComplexMixtures.jl package. The project has great scientific relevance as it provides information about this mechanism of dimerization that would help in understanding how this dimer stabilizes in water and in environments more similar to those found in cells.