title: Loss of conformational entropy in protein folding calculated using realistic ensembles and its implications for NMR-based calculations.
abstract: The loss of conformational entropy is a major contribution in the thermodynamics of protein folding. However, accurate determination of the quantity has proven challenging. We calculate this loss using molecular dynamic simulations of both the native protein and a realistic denatured state ensemble. For ubiquitin, the total change in entropy is TΔSTotal = 1.4 kcal⋅mol(-1) per residue at 300 K with only 20% from the loss of side-chain entropy. Our analysis exhibits mixed agreement with prior studies because of the use of more accurate ensembles and contributions from correlated motions. Buried side chains lose only a factor of 1.4 in the number of conformations available per rotamer upon folding (ΩU/ΩN). The entropy loss for helical and sheet residues differs due to the smaller motions of helical residues (TΔShelix-sheet = 0.5 kcal⋅mol(-1)), a property not fully reflected in the amide N-H and carbonyl C=O bond NMR order parameters. The results have implications for the thermodynamics of folding and binding, including estimates of solvent ordering and microscopic entropies obtained from NMR.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Baxa
authors.affiliation: Biological Sciences Collegiate Division.
authors.forename: Esmael J
authors.initials: EJ
authors.lastname: Haddadian
authors.affiliation: James Franck Institute and Department of Chemistry, and.
authors.forename: John M
authors.initials: JM
authors.lastname: Jumper
authors.affiliation: James Franck Institute and Department of Chemistry, and Computation Institute, The University of Chicago, Chicago, IL 60637 freed@uchicago.edu trsosnic@uchicago.edu.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Freed
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Computation Institute, The University of Chicago, Chicago, IL 60637 freed@uchicago.edu trsosnic@uchicago.edu.
authors.forename: Tobin R
authors.initials: TR
authors.lastname: Sosnick
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D019277:Entropy; D009682:Magnetic Resonance Spectroscopy; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D025801:Ubiquitin / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D025801:Ubiquitin
keywords: NMR order parameters; denatured state; helix propensity; molecular dynamics; sheet propensity