title: Constructing a folding model for protein S6 guided by native fluctuations deduced from NMR structures.
abstract: The diversity in a set of protein nuclear magnetic resonance (NMR) structures provides an estimate of native state fluctuations that can be used to refine and enrich structure-based protein models (SBMs). Dynamics are an essential part of a protein's functional native state. The dynamics in the native state are controlled by the same funneled energy landscape that guides the entire folding process. SBMs apply the principle of minimal frustration, drawn from energy landscape theory, to construct a funneled folding landscape for a given protein using only information from the native structure. On an energy landscape smoothed by evolution towards minimal frustration, geometrical constraints, imposed by the native structure, control the folding mechanism and shape the native dynamics revealed by the model. Native-state fluctuations can alternatively be estimated directly from the diversity in the set of NMR structures for a protein. Based on this information, we identify a highly flexible loop in the ribosomal protein S6 and modify the contact map in a SBM to accommodate the inferred dynamics. By taking into account the probable native state dynamics, the experimental transition state is recovered in the model, and the correct order of folding events is restored. Our study highlights how the shared energy landscape connects folding and function by showing that a better description of the native basin improves the prediction of the folding mechanism.
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, Texas 77005, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Lammert
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, Texas 77005, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Noel
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, Texas 77005, USA.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Haglund
authors.affiliation: Steinbuch Centre for Computing, Karlsruhe Institute of Technology, Karlsruhe, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schug
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, Rice University, Houston, Texas 77005, USA.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
mesh_terms: D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017510:Protein Folding; D038601:Ribosomal Protein S6 / Q000737:chemistry*
chemical_list: D038601:Ribosomal Protein S6