Conformational interconversion in compstatin probed with molecular dynamics simulations
Article first published online: 5 AUG 2003
Copyright © 2003 Wiley-Liss, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 53, Issue 1, pages 130–141, October 2003
How to Cite
Mallik, B., Lambris, J. D. and Morikis, D. (2003), Conformational interconversion in compstatin probed with molecular dynamics simulations. Proteins, 53: 130–141. doi: 10.1002/prot.10491
- Issue published online: 21 AUG 2003
- Article first published online: 5 AUG 2003
- Manuscript Accepted: 14 APR 2003
- Manuscript Received: 24 FEB 2003
- American Heart Association, Western States Affiliate. Grant Number: 0255757Y
- National Institutes of Health. Grant Number: GM 62134
- secondary structure;
- molecular dynamics
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 αR-αR β-turn, as was the conformation of the initial ensemble of NMR structures; 2) β-hairpin with ϵ-αR β-turn; 3) β-hairpin with αR-αR β-turn; 4) β-hairpin with αR-β β-turn; and 5) α-helical. Conformational switch was possible with small amplitude backbone motions of the order of 0.1–0.4 Å and free energy barrier crossing of 2–11 kcal/mol. All of the 21 MD structures corresponding to the NMR ensemble possessed a β-turn, with 14 structures retaining the αR-αR β-turn type, but the average minimized structure and the global optimization structures were converted to α-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. © 2003 Wiley-Liss, Inc.