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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Saraiva Macedo Timmers, Luis Fernando ; Neto, Antonio M. S. ; Montalvao, Rinaldo W. ; Basso, Luiz A. ; Santos, Diogenes S. ; de Souza, Osmar Norberto
Total Authors: 6
Document type: Journal article
Source: Journal of Molecular Modeling; v. 23, n. 7 JUL 2017.
Web of Science Citations: 0

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)

FAPESP's process: 11/11343-0 - Using sparse nuclear magnetic resonance data and comparative modelling for the determination of structure and dynamics of proteins with application in rational drug design
Grantee:Rinaldo Wander Montalvão
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 13/18398-0 - Determination of Protein-Protein and Protein-Ligand Complexes from Sparse Experimental Data
Grantee:Antonio Marinho da Silva Neto
Support type: Scholarships in Brazil - Doctorate