title: Molecular mechanism for stabilizing a short helical peptide studied by generalized-ensemble simulations with explicit solvent.
abstract: 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 alpha-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 alpha-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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. sugita@iam.u-tokyo.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Okamoto
mesh_terms: D000465:Algorithms; D001120:Arginine / Q000737:chemistry; D001703:Biophysics / Q000379:methods*; D002096:C-Peptide / Q000737:chemistry; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D008958:Models, Molecular; D015233:Models, Statistical; D010455:Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry; D025341:Principal Component Analysis; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors; D014867:Water / Q000737:chemistry; D014965:X-Rays
chemical_list: D002096:C-Peptide; D010455:Peptides; D014867:Water; D018698:Glutamic Acid; D010649:Phenylalanine; D006639:Histidine; D001120:Arginine