Unfolding the fold of cyclic cysteine-rich peptides.

We propose a method to extensively characterize the native state ensemble of cyclic cysteine-rich peptides. The method uses minimal information, namely, amino acid sequence and cyclization, as a topological feature that characterizes the native state. The method does not assume a specific disulfide bond pairing for cysteines and allows the possibility of unpaired cysteines. A detailed view of the conformational space relevant for the native state is obtained through a hierarchic multi-resolution exploration. A crucial feature of the exploration is a geometric approach that efficiently generates a large number of distinct cyclic conformations independently of one another. A spatial and energetic analysis of the generated conformations associates a free-energy landscape to the explored conformational space. Application to three long cyclic peptides of different folds shows that the conformational ensembles and cysteine arrangements associated with free energy minima are fully consistent with available experimental data. The results provide a detailed analysis of the native state features of cyclic peptides that can be further tested in experiment.