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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.)

Combining Free Energy Simulations and NMR Chemical-Shift Perturbation To Identify Transient Cation-pi Contacts in Proteins

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Reis, Andre A. O. [1] ; Sayegh, Raphael S. R. [1] ; Marana, Sandro R. [1] ; Arantes, Guilherme M. [1]
Total Authors: 4
[1] Univ Sao Paulo, Inst Quim, Dept Biochem, Av Prof Lineu Prestes 748, BR-05508900 Sao Paulo, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 890-897, FEB 2020.
Web of Science Citations: 1

Flexible protein regions containing cationic and aromatic side-chains exposed to solvent may form transient cation-pi interactions with structural and functional roles. To evaluate their stability and identify important intramolecular cation-pi contacts, a combination of free energy profiles estimated from umbrella sampling with molecular dynamics simulations and chemical shift perturbations (CSP) obtained from nuclear magnetic resonance (NMR) experiments is applied here to the complete catalytic domain of human phosphatase Cdc25B. This protein is a good model system for transient cation-pi interactions as it contains only one Trp residue (W550) in the disordered C-terminal segment and a total of 17 Arg residues, many exposed to solvent. Eight putative Arg-Trp pairs were simulated here. Only R482 and R544 show bound profiles corresponding to important transient cation-pi interactions, while the others have dissociative or almost flat profiles. These results are corroborated by CSP analysis of three Cdc25B point mutants (W550A, R482A, and R544A) disrupting cation-pi contacts. The proposed validation of statistically representative molecular simulations by NMR spectroscopy could be applied to identify transient contacts of proteins in general but carefully, as NMR chemical shifts are sensitive to changes in both molecular contacts and conformational distributions. (AU)

FAPESP's process: 18/25952-8 - Catalysis and Thermostability in Enzymes: Oligomerization, Structure Network and Dynamics Effects
Grantee:Sandro Roberto Marana
Support type: Regular Research Grants
FAPESP's process: 16/24096-5 - Computer simulation of metalloenzymes and of flexible proteins
Grantee:Guilherme Menegon Arantes
Support type: Regular Research Grants
FAPESP's process: 18/08311-9 - Computational bioinorganic chemistry & high-performance computing
Grantee:Guilherme Menegon Arantes
Support type: Regular Research Grants
FAPESP's process: 12/00543-1 - Inhibitors Recognition and Flexibility of Cdc25B Phosphatase
Grantee:Raphael Santa Rosa Sayegh
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 16/22365-9 - Enzyme structural network and dynamics
Grantee:Sandro Roberto Marana
Support type: Regular Research Grants