title: Evaluating the stability of disulfide bridges in proteins: a torsional potential energy surface for diethyl disulfide.
abstract: Disulfide bonds formed by the oxidation of cysteine residues in proteins are the major form of intra- and inter-molecular covalent linkages in the polypeptide chain. To better understand the conformational energetics of this linkage, we have used the MP2(full)/6-31G(d) method to generate a full potential energy surface (PES) for the torsion of the model compound diethyl disulfide (DEDS) around its three critical dihedral angles (χ2, χ3, χ2'). The use of ten degree increments for each of the parameters resulted in a continuous, fine-grained surface. This allowed us to accurately predict the relative stabilities of disulfide bonds in high resolution structures from the Protein Data Bank. The MP2(full) surface showed significant qualitative differences from the PES calculated using the Amber force field. In particular, a different ordering was seen for the relative energies of the local minima. Thus, Amber energies are not reliable for comparison of the relative stabilities of disulfide bonds. Surprisingly, the surface did not show a minimum associated with χ2∼ - 60°, χ3∼ 90, χ2' ∼ - 60°. This is due to steric interference between Hα atoms. Despite this, significant populations of disulfides were found to adopt this conformation. In most cases this conformation is associated with an unusual secondary structure motif, the cross-strand disulfide. The relative instability of cross-strand disulfides is of great interest, as they have the potential to act as functional switches in redox processes.
authors: Structural and Computational Biology Program, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia ; Computer-Chemie-Centrum, University of Erlangen-Nuremberg, Nägelsbachstrasse 25, 91052 Erlangen, Germany.
authors: N L
authors: NL
authors: Haworth
authors: Computational Proteomics Group, John Curtin School of Medical Research, GPO Box 334, Canberra City ACT 2601, Australia.
authors: J E
authors: JE
authors: Gready
authors: Structural and Computational Biology Program, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
authors: R A
authors: RA
authors: George
authors: Structural and Computational Biology Program, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia ; School of Biotechnology and Biomolecular Sciences, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
authors: M A
authors: MA
authors: Wouters
keywords: Arsenate reductase; Diethyl disulfide; Disulfide bond; Potential energy surface; Redox activity; Stability prediction