title: Preferred Hydrogen-Bonding Partners of Cysteine: Implications for Regulating Cys Functions.
abstract: The hydrogen-bonding interactions of cysteine, which can serve as a hydrogen-bond donor and/or acceptor, play a central role in cysteine's diverse functional roles in proteins. They affect the balance between the neutral thiol (SH) or thiolate (S-) and the charge distribution in the rate-limiting transition state of a reaction. Despite their importance, no study has determined the preferred hydrogen-bonding partners of cysteine serving as a hydrogen-bond donor or acceptor. By computing the free energy for displacing a peptide backbone hydrogen-bonded to cysteine with amino acid side chains in various protein environments, we have evaluated how the strength of the hydrogen bond to the cysteine thiol/thiolate depends on its hydrogen-bonding partner and its local environment. The predicted hydrogen-bonding partners preferred by cysteine are consistent with the hydrogen-bonding interactions made by cysteines in 9138 nonredundant X-ray structures. Our results suggest a mechanism to regulate the reactivity of cysteines and a strategy to design drugs based on the hydrogen-bonding preference of cysteine.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.|Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica , Taipei 11529, Taiwan.|Institute of Biochemical Sciences, National Taiwan University , Taipei 10617, Taiwan.
authors.forename: Karine
authors.initials: K
authors.lastname: Mazmanian
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Karen
authors.initials: K
authors.lastname: Sargsyan
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.
authors.forename: Cédric
authors.initials: C
authors.lastname: Grauffel
authors.affiliation: Faculty of Chemistry and Pharmacy, Sofia University , Sofia 1164, Bulgaria.
authors.forename: Todor
authors.initials: T
authors.lastname: Dudev
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 11529, Taiwan.|Department of Chemistry, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D013816:Thermodynamics
chemical_list: D003545:Cysteine