title: The unfolded ensemble and folding mechanism of the C-terminal GB1 beta-hairpin.
abstract: In this work, we shed new light on a much-studied case of beta-hairpin folding by means of advanced molecular dynamics simulations. A fully atomistic description of the protein and the solvent molecule is used, together with metadynamics, to accelerate the sampling and estimate free-energy landscapes. This is achieved using the path collective variables approach, which provides an adaptive description of the mechanism under study. We discover that the folding mechanism is a multiscale process where the turn region conformation leads to two different energy pathways that are connected by elongated structures. The former displays a stable 2:4 native-like structure in which an optimal hydrophobic packing and hydrogen bond pattern leads to 8 kcal/mol of stabilization. The latter shows a less-structured 3:5 beta-sheet, where hydrogen bonds and hydrophobic packing provide only 2.5 kcal/mol of stability. This perspective is fully consistent with experimental evidence that shows this to be a prototypical two-state folder, while it redefines the nature of the unfolded state.
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, ETH Zürich, USI Campus, Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bonomi
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Francesco L
authors.initials: FL
authors.lastname: Gervasio
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry*; D003198:Computer Simulation; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus