Conformational interconversion in compstatin probed with molecular dynamics simulations

Compstatin is a 13-residue cyclic peptide that has the potential to become a therapeutic agent against unregulated complement activation. In our effort to understand the structural and dynamic characteristics of compstatin that form the basis for rational and combinatorial optimization of structure and activity, we performed 1-ns molecular dynamics (MD) simulations. We used as input in the MD simulations the ensemble of 21 lowest energy NMR structures, the average minimized structure, and a global optimization structure. At the end of the MD simulations we identified five conformations, with populations ranging between 9% and 44%. These conformations are as follows: 1) coil with alpha(R)-alpha(R) beta-turn, as was the conformation of the initial ensemble of NMR structures; 2) beta-hairpin with E-U, beta-turn; 3) beta-hairpin with alpha(R)-alpha(R) beta-turn; 4) beta-hairpin with alpha(R)-beta beta-turn; and 5) alpha-helical. Conformational switch was possible with small amplitude backbone motions of the order of 0.1-0.4 Angstrom and free energy barrier crossing of 2-11 kcal/mol. All of the 21 MD structures corresponding to the NMR ensemble possessed a beta-turn, with 14 structures retaining the alpha(R)-alpha(R) beta-turn type, but the average minimized structure and the global optimization structures were converted to a-helical conformations. Overall, the MD simulations have aided to gain insight into the conformational. space sampled by compstatin and have provided a measure of conformational interconversion. The calculated conformers will be useful as structural and possibly dynamic templates for optimization in the design of compstatin using structure-activity relations (SAR) or dynamics-activity relations (DAR). Proteins 2003;52:130-141. (C) 2003 Wiley-Liss, Inc.