EPSP synthase flexibility is determinant to its function: computational molecular dynamics and metadynamics studies

Autor(es)

Saraiva Macedo Timmers, Luis Fernando ; Neto, Antonio M. S. ; Montalvao, Rinaldo W. ; Basso, Luiz A. ; Santos, Diogenes S. ; de Souza, Osmar Norberto

• Tipo de documento: Artigo Científico
• Fonte: Journal of Molecular Modeling; v. 23, n. 7 JUL 2017.
• Citações Web of Science: 0

Resumo

Flexibility is involved in a wide range of biological processes, such as protein assembly and binding recognition. EPSP synthase is an enzyme that must undergo a large conformational change to accommodate its ligands into its binding cavity. However, although the structure of EPSP synthase has been determined, its plasticity has not been explored in depth. Therefore, in this work, we extensively examined the influence of the flexibility of Mycobacterium tuberculosis EPSP (MtEPSP) synthase on the function of this protein using classical and replica-exchange metadynamics simulations. We were able to identify five well-populated conformational clusters for MtEPSP synthase: two corresponding to open, one to ajar, and two to closed conformations. We also pinpointed three hydrophobic regions that are responsible for guiding transitions among these states. Taken together, the new findings presented here indicate how the hydrophobic regions modulate the flexibility of MtEPSP synthase, and they highlight the importance of considering these dynamic features in drug design projects employing this enzyme as a target. (AU)

• Processo FAPESP: 11/11343-0 - Usando dados esparsos de ressonância magnética nuclear e modelagem comparativa para determinar estrutura e dinâmica de proteínas com aplicação em desenho racional de drogas
• Beneficiário: Rinaldo Wander Montalvão
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/18398-0 - Determinação de Complexos entre Proteínas e Ligantes usando Dados Experimentais Esparsos
• Beneficiário: Antonio Marinho da Silva Neto
• Modalidade de apoio: Bolsas no Brasil - Doutorado