title: Identification of allosteric disulfides from prestress analysis.
abstract: Disulfide bonds serve to form physical cross-links between residues in protein structures, thereby stabilizing the protein fold. Apart from this purely structural role, they can also be chemically active, participating in redox reactions, and they may even potentially act as allosteric switches controlling protein functions. Specific types of disulfide bonds have been identified in static protein structures from their distinctive pattern of dihedral bond angles, and the allosteric function of such bonds is purported to be related to the torsional strain they store. Using all-atom molecular-dynamics simulations for ∼700 disulfide bonded proteins, we analyzed the intramolecular mechanical forces in 20 classes of disulfide bonds. We found that two particular classes, the -RHStaple and the -/+RHHook disulfides, are indeed more stressed than other disulfide bonds, but the stress is carried primarily by stretching of the S-S bond and bending of the neighboring bond angles, rather than by dihedral torsion. This stress corresponds to a tension force of magnitude ∼200 pN, which is balanced by repulsive van der Waals interactions between the cysteine Cα atoms. We confirm stretching of the S-S bond to be a general feature of the -RHStaples and the -/+RHHooks by analyzing ∼20,000 static protein structures. Given that forced stretching of S-S bonds is known to accelerate their cleavage, we propose that prestress of allosteric disulfide bonds has the potential to alter the reactivity of a disulfide, thereby allowing us to readily switch between functional states.
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Beifei
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
authors.forename: Ilona B
authors.initials: IB
authors.lastname: Baldus
authors.affiliation: Heidelberg Institute for Theoretical Studies, Heidelberg, Germany; Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Li
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China; College of Physics Science and Technology, Shenzhen University, Shenzhen, Guangdong, China.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Edwards
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai, China; Heidelberg Institute for Theoretical Studies, Heidelberg, Germany. Electronic address: frauke.graeter@h-its.org.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D014841:von Willebrand Factor / Q000737:chemistry*
chemical_list: D015704:CD4 Antigens; D004220:Disulfides; D014841:von Willebrand Factor
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