Molecular mechanism for stabilizing a short helical peptide studied by generalized-ensemble simulations with explicit solvent

¹ University of Tokyo
² Institute for Molecular Science

^* To whom correspondence should be addressed. E-mail: sugita{at}iam.u-tokyo.ac.jp.

Submitted on July 11, 2004
Revised on September 14, 2004
Accepted on 10 February 2005

	Abstract

We study the folding mechanism of an analogue 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 a-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 towards the C-terminal end, whereas the salt bridge between Glu--2 and Arg+-10 mainly works as a restraint to prevent the a-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.

Key Words: Cpeptide of ribonuclease A, consistency principle, generalized-ensemble algorithms, principle of minimal frustration, protein folding