title: First-principles calculation of the folding free energy of a three-helix bundle protein.
abstract: The folding and unfolding of a three-helix bundle protein were explored with molecular-dynamics simulations, cluster analysis, and weighted-histogram techniques. The folding-unfolding process occurs by means of a "folding funnel," in which a uniform and broad distribution of conformational states is accessible outside of the native manifold. This distribution narrows near a transition region and becomes compact within the native manifold. Key thermodynamic steps in folding include initial interactions around the amino-terminal helix-turn-helix motif, interactions between helices I and II, and, finally, the docking of helix III onto the helix I-II subdomain. A metastable minimum in the calculated free-energy surface is observed at approximately 1.5 times the native volume. Folding-unfolding thermodynamics are dominated by the opposing influences of protein-solvent energy, which favors unfolding, and the overall entropy, which favors folding by means of the hydrophobic effect.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Boczko
authors.forename: C L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D000595:Amino Acid Sequence; D003196:Computer Graphics; D018257:Helix-Loop-Helix Motifs; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013205:Staphylococcal Protein A / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D010446:Peptide Fragments; D013205:Staphylococcal Protein A