Empirical modifications to the Amber/OPLS potential for predicting the solution conformations of cyclic peptides by...

Peptides have ubiquitous roles in all biological systems and are thus of interest in both basic and applied research. The rational design of bioactive peptides could be greatly enhanced by an efficient method for accurately predicting the conformations that these molecules can adopt in solution. As a design process inevitably requires testing numerous molecules, an efficient method would require the calculations to be performed in vacuum.

Attempts to predict the conformations of cyclic peptides using a simulated annealing protocol with the Amber/OPLS potential in vacuum resulted, not unexpectedly, in overly packed, non-native conformations. We therefore empirically modified the potential by several cycles of structure prediction and function refinement until a good fit between experimental and predicted conformations was obtained. Three major modifications to the potential were required in order to reproduce the solution structures of cyclic peptides: explicit torsional energies for the peptide backbone torsional angles; explicit hydrogen-bonding energies for backbone hydrogen bonds; and a penalty for close approaches between uncharged and charged atoms.

Using the modified potential, we predicted the solution conformations of cyclic peptides in the size range of 5-10 residues with reasonable accuracy.