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Characterization of conformational changes in the globular domain of the M2-1 protein of hRSV and hMPV: mechanisms involving open-closed equilibrium and implications.

Grant number: 23/09642-7
Support Opportunities:Scholarships in Brazil - Support Program for Fixating Young Doctors
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2024
Field of knowledge:Physical Sciences and Mathematics - Physics - Condensed Matter Physics
Acordo de Cooperação: CNPq
Principal Investigator:Ícaro Putinhon Caruso
Grantee:Raphael Vinicius Rodrigues Dias
Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
Associated research grant:23/01632-2 - Characterization of conformational changes in the globular domain of the M2-1 protein of hRSV and hMPV: mechanisms involving open-closed equilibrium and implications, AP.R

Abstract

Human Respiratory Syncytial Virus (hRSV) and Human Metapneumovirus (hMPV) are the most common pathological agents of respiratory diseases in newborns, children and the elderly, causing diseases such as bronchiolitis and pneumonia. Among various proteins encoded by viruses, M2-1 stands out for acting as a transcriptional cofactor that prevents premature dissociation of the polymerase complex, and that its poor functionality affects the viral replicative cycle. Structurally, M2-1 is a multidomain protein formed by four monomeric subunits, which are composed of four different domains. Recent studies show that the three-dimensional rearrangement of the subunits is flexible, presenting "open" and "closed" conformations, giving it a new dynamic feature to M2-1 action and allows, for example, its simultaneous interaction with the viral phosphoprotein and mRNA. Furthermore, it is reported that the stability of both conformations and the balance between them are crucial for its functioning. In this context, the present project aims to computationally model and characterize the conformational changes between open and closed states of the M2-1 proteins of hRSV and hMPV using minimalist models to sample the conformational dynamics between these different conformations. From the obtained data, it is possible to refine the model and use it as a starting point for the elucidation of mechanisms concerning these transitions, and to identify target regions for mutations and rational drug design. The lack of a comprehensive molecular understanding of the functions associated with the conformational dynamics of M2-1 highlights the importance of this project. Our findings will contribute to a deeper understanding of M2-1 role in the viral transcription process and inform the development of new strategies to combat these viruses by interrupting their replication cycles.

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