title: Simple physical models connect theory and experiment in protein folding kinetics.
abstract: Our understanding of the principles underlying the protein-folding problem can be tested by developing and characterizing simple models that make predictions which can be compared to experimental data. Here we extend our earlier model of folding free energy landscapes, in which each residue is considered to be either folded as in the native state or completely disordered, by investigating the role of additional factors representing hydrogen bonding and backbone torsion strain, and by using a hybrid between the master equation approach and the simple transition state theory to evaluate kinetics near the free energy barrier in greater detail. Model calculations of folding phi-values are compared to experimental data for 19 proteins, and for more than half of these, experimental data are reproduced with correlation coefficients between r=0.41 and 0.88; calculations of transition state free energy barriers correlate with rates measured for 37 single domain proteins (r=0.69). The model provides insight into the contribution of alternative-folding pathways, the validity of quasi-equilibrium treatments of the folding landscape, and the magnitude of the Arrhenius prefactor for protein folding. Finally, we discuss the limitations of simple native-state-based models, and as a more general test of such models, provide predictions of folding rates and mechanisms for a comprehensive set of over 400 small protein domains of known structure.
authors.affiliation: Lawrence Berkeley National Lab, Physical Biosciences Division, Berkeley, CA 94720, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Alm
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Morozov
authors.forename: Tanja
authors.initials: T
authors.lastname: Kortemme
authors.forename: David
authors.initials: D
authors.lastname: Baker
mesh_terms: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D005288:Ferredoxins / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D000072236:Methyl-Accepting Chemotaxis Proteins; D008956:Models, Chemical; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism; D012260:Ribonucleases / Q000737:chemistry / Q000378:metabolism; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D018909:src Homology Domains
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D005288:Ferredoxins; C029152:G-substrate; C116593:L-protein, Peptococcus magnus; D008565:Membrane Proteins; D000072236:Methyl-Accepting Chemotaxis Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; D022061:Tacrolimus Binding Protein 1A