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.
Highlights
Disulfide bonds between oxidised cysteine residues are generally viewed as structurally stabilising elements in proteins
The Hartree –Fock (HF) and MP2(full) results are the same as those described by Gorbitz [9] and have been included here for comparison
The relative stabilities of the minima on the MP2(full) surface were found to be in good agreement with the G3X benchmark calculations, whereas the Amber force field gave large deviations in the relative energies and a different order for the stabilities of the conformations
Summary
Disulfide bonds between oxidised cysteine residues are generally viewed as structurally stabilising elements in proteins. A new role for a subset of disulfides as redox switches is emerging. Redox switching of disulfide bonds has been demonstrated in both reversible and irreversible redox regulation of proteins. Reversible systems include those involved in redox signalling such as the peroxide sensor, OxyR, where disulfidebond formation activates the transcription factor in response to oxidative stress [1]. Irreversible redox regulation mediated by disulfide reduction and subsequent irreversible conformational change has been described. Reduction of disulfides and subsequent cleavage of protein chains has been demonstrated in ovotransferrin and plasmin [2,3] and is likely to be an important regulatory mechanism for many other proteins
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