Disulfide bridges, a common type of covalent bond in protein structures, are usually believed to maintain structural stability of proteins, especially small peptides that lack hydrophobic cores. Our study, in this April 26 issue of Biophysical Journal, revealed that disulfide bridges are also critical, at least in the case of the MCoTI-II peptide, for holding together a native structure that is frustrated.
The cover image shows the native structure (left) as well as snapshots from folding/unfolding molecular dynamics simulations of the cyclic peptide named MCoTI-II, which acts as a trypsin inhibitor in plants and has three disulfide bonds in its native state (red, green, and blue). In the context of its folding funnel, our simulations showed that the peptide is frustrated near the bottom of the funnel (native structure, middle), but not as frustrated higher up in the funnel (unfolded states, right). The formation of two of the three disulfide bridges was found to be anti-correlated when the peptide approaches the native state, yet both are critical for snapping the frustrated native structure into place. The protein structures in the cover image are visualized through VMD (http://www.ks.uiuc.edu/Research/vmd/).
When the sequence of protein isn’t perfect for folding, perhaps as a result of evolution for function, disulfide bridges can play a role holding together a frustrated structure that cannot form otherwise. Furthermore, due to the extreme stability and interesting biological activities of cyclotides such as MCoTI-II, our studies may also shed light on engineering cyclotides as novel pharmaceuticals in the future.
-Yi Zhang, Paramjit S. Bansal, David Wilson, Klaus Schulten, Martin Gruebele, Norelle L. Daly