title: A tool set to map allosteric networks through the NMR chemical shift covariance analysis.
abstract: Allostery is an essential regulatory mechanism of biological function. Allosteric sites are also pharmacologically relevant as they are often targeted with higher selectivity than orthosteric sites. However, a comprehensive map of allosteric sites poses experimental challenges because allostery is driven not only by structural changes, but also by modulations in dynamics that typically remain elusive to classical structure determination methods. An avenue to overcome these challenges is provided by the NMR chemical shift covariance analysis (CHESCA), as chemical shifts are exquisitely sensitive to redistributions in dynamic conformational ensembles. Here, we propose a set of complementary CHESCA algorithms designed to reliably detect allosteric networks with minimal occurrences of false positives or negatives. The proposed CHESCA toolset was tested for two allosteric proteins (PKA and EPAC) and is expected to complement traditional comparative structural analyses in the comprehensive identification of functionally relevant allosteric sites, including those in otherwise elusive partially unstructured regions.
authors.affiliation: Departments of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Boulton
authors.affiliation: Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Madoka
authors.initials: M
authors.lastname: Akimoto
authors.affiliation: Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Rajeevan
authors.initials: R
authors.lastname: Selvaratnam
authors.affiliation: Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Amir
authors.initials: A
authors.lastname: Bashiri
authors.affiliation: 1] Departments of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada [2] Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D000465:Algorithms; D000494:Allosteric Regulation; D000495:Allosteric Site; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D015203:Reproducibility of Results