A Threshold-Minimization Scheme for Exploring the Energy Landscape of Biomolecules: Application to a Cyclic Peptide and a Disaccharide

We present a scheme, called the threshold-minimization method, for globally exploring the energy landscapes of small systems of biomolecular interest where typical exploration moves always require a certain degree of subsequent structural relaxation in order to be efficient, e.g., systems containing small or large circular carbon chains such as cyclic peptides or carbohydrates. We show that using this threshold-minimization method we can not only reproduce the global minimum and relevant local minima but also overcome energetic barriers associated with different types of isomerism for the example of a cyclic peptide, cyclo-(Gly)4. We then apply the new method to the disaccharide α-d-glucopyranose-1–2-β-d-fructofuranose, report energetically preferred configurations and barriers to boat–chair isomerization in the glucopyranosyl ring, and discuss the energy landscape.