title: Probing the Unfolded Configurations of a β-Hairpin Using Sketch-Map.
abstract: This work examines the conformational ensemble involved in β-hairpin folding by means of advanced molecular dynamics simulations and dimensionality reduction. A fully atomistic description of the protein and the surrounding solvent molecules is used, and this complex energy landscape is sampled by means of parallel tempering metadynamics simulations. The ensemble of configurations explored is analyzed using the recently proposed sketch-map algorithm. Further simulations allow us to probe how mutations affect the structures adopted by this protein. We find that many of the configurations adopted by a mutant are the same as those adopted by the wild-type protein. Furthermore, certain mutations destabilize secondary-structure-containing configurations by preventing the formation of hydrogen bonds or by promoting the formation of new intramolecular contacts. Our analysis demonstrates that machine-learning techniques can be used to study the energy landscapes of complex molecules and that the visualizations that are generated in this way provide a natural basis for examining how the stabilities of particular configurations of the molecule are affected by factors such as temperature or structural mutations.
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich , USI-Campus, Via Giuseppe Buffi 13, C-6900 Lugano, Switzerland.
authors.forename: Albert
authors.initials: A
authors.lastname: Ardevol
authors.affiliation: Atomistic Simulation Centre, School of Mathematics and Physics, Queen's University Belfast , Belfast BT7 1NN, United Kingdom.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Tribello
authors.affiliation: Laboratory of Computational Science and Modelling, EPFL , CH-1015 Lausanne, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceriotti
authors.affiliation: Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich , USI-Campus, Via Giuseppe Buffi 13, C-6900 Lugano, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Parrinello
mesh_terms: D000465:Algorithms; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins