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Molecular Mechanism for Stabilizing a Short Helical Peptide Studied by Generalized-Ensemble Simulations with Explicit Solvent

Yuji Sugita ^* and Yuko Okamoto  

^* Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Theoretical Studies, Institute for Molecular Science, Okazaki, Aichi 444-8585, Japan; and Department of Functional Molecular Science, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8585, Japan

Correspondence: Address reprint requests to Yuji Sugita, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: 81-3-5841-8493; Fax: 81-3-5841-8493; E-mail: sugita{at}iam.u-tokyo.ac.jp.

We study the folding mechanism of an analog of the C-peptide of ribonuclease A in explicit water by a replica-exchange multicanonical molecular dynamics simulation based on all-atom models. The multicanonical weight factor was determined by the combined use of the multicanonical replica-exchange method and the replica-exchange multicanonical algorithm. Using statistically reliable data thus obtained, we have examined the free-energy landscape of the peptide system. The global-minimum free-energy state in the landscape at room temperature has an -helix structure with a distortion near the N-terminus. The state also has a salt bridge between Glu^–-2 and Arg⁺-10 and an aromatic-aromatic interaction between Phe-8 and His⁺-12, both of which have been observed in x-ray and other experimental measurements. Principal component analysis clearly shows the different roles of these side-chain interactions in the peptide folding. The side-chain interaction between Phe-8 and His⁺-12 greatly enhances the stability of helical structure toward the C-terminal end, whereas the salt bridge between Glu^–-2 and Arg⁺-10 mainly works as a restraint to prevent the -helix structure from extending to the N-terminus. The free-energy landscape of C-peptide reveals a funnel-like shape where all of these interactions consistently exist only in the global-minimum state. This is the major reason why the native structure of the short helical peptide shows significant stability at low temperatures.