First-Principles Calculation of the Folding Free Energy of a Three-Helix Bundle Protein

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...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 1995-07, Vol.269 (5222), p.393-396
Main Authors: Boczko, Erik M., Brooks, Charles L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Analytical, structural and metabolic biochemistry
Biological and medical sciences
Computation
Computer Graphics
Conformity
Coordinate systems
Energy
Entropy
Folding tables
Free energy
Fundamental and applied biological sciences. Psychology
General aspects, investigation methods
Helix-Loop-Helix Motifs
Hydrogen bonds
Inhalants
Modeling
Models, Molecular
Molecular biology
Molecular Sequence Data
Peptide Fragments - chemistry
Protein Folding
Protein Structure, Secondary
Proteins
Sampling
Scientific Concepts
Solvents
Staphylococcal Protein A - chemistry
Structural Elements (Construction)
Thermodynamics
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Summary: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 proteinsolvent energy, which favors unfolding, and the overall entropy, which favors folding by means of the hydrophobic effect.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.7618103