title: Structural origin of slow diffusion in protein folding.
abstract: Experimental, theoretical, and computational studies of small proteins suggest that interresidue contacts not present in the folded structure play little or no role in the self-assembly mechanism. Non-native contacts can, however, influence folding kinetics by introducing additional local minima that slow diffusion over the global free-energy barrier between folded and unfolded states. Here, we combine single-molecule fluorescence with all-atom molecular dynamics simulations to discover the structural origin for the slow diffusion that markedly decreases the folding rate for a designed α-helical protein. Our experimental determination of transition path times and our analysis of the simulations point to non-native salt bridges between helices as the source, which provides a quantitative glimpse of how specific intramolecular interactions influence protein folding rates by altering dynamics and not activation free energies.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0520, USA. chunghoi@niddk.nih.gov stefano.piana-agostinetti@DEShawResearch.com david.shaw@DEShawResearch.com eaton@helix.nih.gov.
authors.forename: Hoi Sung
authors.initials: HS
authors.lastname: Chung
authors.affiliation: D. E. Shaw Research, New York, NY 10036, USA. chunghoi@niddk.nih.gov stefano.piana-agostinetti@DEShawResearch.com david.shaw@DEShawResearch.com eaton@helix.nih.gov.
authors.forename: Stefano
authors.initials: S
authors.lastname: Piana-Agostinetti
authors.affiliation: D. E. Shaw Research, New York, NY 10036, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. chunghoi@niddk.nih.gov stefano.piana-agostinetti@DEShawResearch.com david.shaw@DEShawResearch.com eaton@helix.nih.gov.
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892-0520, USA. chunghoi@niddk.nih.gov stefano.piana-agostinetti@DEShawResearch.com david.shaw@DEShawResearch.com eaton@helix.nih.gov.
authors.forename: William A
authors.initials: WA
authors.lastname: Eaton
mesh_terms: D004058:Diffusion; D019277:Entropy; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*
chemical_list: D011506:Proteins