title: Complex folding pathways in a simple beta-hairpin.
abstract: The determination of the folding mechanisms of proteins is critical to understand the topological change that can propagate Alzheimer and Creutzfeld-Jakobs diseases, among others. The computational community has paid considerable attention to this problem; however, the associated time scale, typically on the order of milliseconds or more, represents a formidable challenge. Ab initio protein folding from long molecular dynamics simulations or ensemble dynamics is not feasible with ordinary computing facilities and new techniques must be introduced. Here we present a detailed study of the folding of a 16-residue beta-hairpin, described by a generic energy model and using the activation-relaxation technique. From a total of 90 trajectories at 300 K, three folding pathways emerge. All involve a simultaneous optimization of the complete hydrophobic and hydrogen bonding interactions. The first two pathways follow closely those observed by previous theoretical studies (folding starting at the turn or by interactions between the termini). The third pathway, never observed by previous all-atom folding, unfolding, and equilibrium simulations, can be described as a reptation move of one strand of the beta-sheet with respect to the other. This reptation move indicates that non-native interactions can play a dominant role in the folding of secondary structures. Furthermore, such a mechanism mediated by non-native hydrogen bonds is not available for study by unfolding and Gō model simulations. The exact folding path followed by a given beta-hairpin is likely to be influenced by its sequence and the solvent conditions. Taken together, these results point to a more complex folding picture than expected for a simple beta-hairpin.
authors.affiliation: Département de physique and Regroupement québécois sur les matériaux de pointe, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wei
authors.forename: Normand
authors.initials: N
authors.lastname: Mousseau
authors.forename: Philippe
authors.initials: P
authors.lastname: Derreumaux
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D016000:Cluster Analysis; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins; C034284:IgG Fc-binding protein, Streptococcus