EPSP synthase flexibility is determinant to its function: computational molecular dynamics and metadynamics studies.
| Title: | EPSP synthase flexibility is determinant to its function: computational molecular dynamics and metadynamics studies. |
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| Authors: | Timmers LFSM; Laboratory for Bioinformatics, Modelling and Simulation of Biosystems (LABIO), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681 - LABIO, Prédio 32, Sala 602, Partenon, Porto Alegre, RS, CEP: 90619-900, Brazil.; Laboratory of PharmInformatics, PUCRS, Porto Alegre, RS, Brazil.; Graduate Program in Cellular and Molecular Biology (PPGBCM), PUCRS, Porto Alegre, RS, Brazil.; Research Centre of Molecular and Functional Biology (CPBMF), PUCRS, Porto Alegre, RS, Brazil.; Graduate Program in Medicine and Health Sciences (PPGMCS), PUCRS, Porto Alegre, RS, Brazil.; Neto AMS; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.; Montalvão RW; São Carlos Institute of Physics, University of São Paulo, São Carlos, SP, Brazil.; Basso LA; Graduate Program in Cellular and Molecular Biology (PPGBCM), PUCRS, Porto Alegre, RS, Brazil.; Research Centre of Molecular and Functional Biology (CPBMF), PUCRS, Porto Alegre, RS, Brazil.; Graduate Program in Medicine and Health Sciences (PPGMCS), PUCRS, Porto Alegre, RS, Brazil.; Santos DS; Graduate Program in Cellular and Molecular Biology (PPGBCM), PUCRS, Porto Alegre, RS, Brazil.; Research Centre of Molecular and Functional Biology (CPBMF), PUCRS, Porto Alegre, RS, Brazil.; Norberto de Souza O; Laboratory for Bioinformatics, Modelling and Simulation of Biosystems (LABIO), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6681 - LABIO, Prédio 32, Sala 602, Partenon, Porto Alegre, RS, CEP: 90619-900, Brazil. osmar.norberto@pucrs.br.; Laboratory of PharmInformatics, PUCRS, Porto Alegre, RS, Brazil. osmar.norberto@pucrs.br.; Graduate Program in Cellular and Molecular Biology (PPGBCM), PUCRS, Porto Alegre, RS, Brazil. osmar.norberto@pucrs.br.; Research Centre of Molecular and Functional Biology (CPBMF), PUCRS, Porto Alegre, RS, Brazil. osmar.norberto@pucrs.br. |
| Source: | Journal of molecular modeling [J Mol Model] 2017 Jul; Vol. 23 (7), pp. 197. Date of Electronic Publication: 2017 Jun 07. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Springer Country of Publication: Germany NLM ID: 9806569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 0948-5023 (Electronic) Linking ISSN: 09485023 NLM ISO Abbreviation: J Mol Model Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Berlin : Springer, c1996- |
| MeSH Terms: | 3-Phosphoshikimate 1-Carboxyvinyltransferase/*chemistry ; Bacterial Proteins/*chemistry ; Mycobacterium tuberculosis/*enzymology; Protein Domains ; Structure-Activity Relationship |
| Abstract: | 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. Graphical abstract The flexibility of EPSP synthase as a function of the pincer angles. |
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| Contributed Indexing: | Keywords: Classical molecular dynamics; EPSP synthase; Protein flexibility; Replica-exchange metadynamics simulations |
| Substance Nomenclature: | 0 (Bacterial Proteins); EC 2.5.1.19 (3-Phosphoshikimate 1-Carboxyvinyltransferase) |
| Entry Date(s): | Date Created: 20170608 Date Completed: 20180829 Latest Revision: 20181113 |
| Update Code: | 20260130 |
| DOI: | 10.1007/s00894-017-3372-2 |
| PMID: | 28589464 |
| Database: | MEDLINE |
Journal Article