title: Understanding the roles of amino acid residues in tertiary structure formation of chignolin by using molecular dynamics simulation.
abstract: Chignolin is a 10-residue peptide (GYDPETGTWG) that forms a stable beta-hairpin structure in water. However, its design template, GPM12 (GYDDATKTFG), does not have a specific structure. To clarify which amino acids give it the ability to form the beta-hairpin structure, we calculated the folding free-energy landscapes of chignolin, GPM12, and their chimeric peptides using multicanonical molecular dynamics (MD) simulation. Cluster analysis of the conformational ensembles revealed that the native structure of chignolin was the lowest in terms of free energy while shallow local minima were widely distributed in the free energy landscape of GPM12, in agreement with experimental observations. Among the chimeric peptides, GPM12(D4P/K7G) stably formed the same beta-hairpin structure as that of chignolin in the MD simulation. This was confirmed by nuclear magnetic resonance (NMR) spectroscopy. A comparison of the free-energy landscapes showed that the conformational distribution of the Asp3-Pro4 sequence was inherently biased in a way that is advantageous both to forming hydrogen bonds with another beta-strand and to initiating loop structure. In addition, Gly7 helps stabilize the loop structure by having a left-handed alpha-helical conformation. Such a conformation is necessary to complete the loop structure, although it is not preferred by other amino acids. Our results suggest that the consistency between the short-range interactions that determine the local geometries and the long-range interactions that determine the global structure is important for stable tertiary structure formation.
authors.affiliation: Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. tterada@iu.a.u-tokyo.ac.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Terada
authors.forename: Daisuke
authors.initials: D
authors.lastname: Satoh
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Mikawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Ito
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shimizu
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D003198:Computer Simulation; D005287:Ferredoxin-NADP Reductase / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D013997:Time Factors
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D011994:Recombinant Proteins; C506175:chignolin; D005287:Ferredoxin-NADP Reductase