Crystallographic B-Factors Highlight Energetic Frustration in Aldolase Folding

• Published in: The journal of physical chemistry. B Vol. 112; no. 34; pp. 10417 - 10431
• Main Authors: Rao, Maithreyi K, Chapman, Tracy R, Finke, John M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.08.2008
• Subjects: Algorithms; Animals; B: Macromolecules, Soft Matter; Computer Simulation; Crystallography, X-Ray; Fructose-Bisphosphate Aldolase - chemistry; Kinetics; Models, Molecular; Protein Conformation; Protein Folding; Protein Structure, Secondary; Rabbits; Thermodynamics
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp7117295

Kinetic simulations of the folding and unfolding of the mammalian TIM barrel protein aldolase were conducted to determine if a minimalist monomeric Go̅ model, using the native structure to determine attractive energies in the protein chain, could capture the experimentally determined folding pathway. The folding order, that is, the order in which different secondary structures fold, between the Go̅ model simulations and that from hydrogen−deuterium exchange experiments, did not agree. To explain this discrepancy, two alternate variant of the basic Go̅ model were simulated: (1) a monomer Go̅ model with native contact energies weighted by a statistical potential (SP model) and (2) a monomer Go̅ model with native contact energies inversely weighted by crystallographic B factors (B model). The B model demonstrated the best agreement between simulation and experiments. The success of the B model is attributed to the ability of B factors to highlight local energetic frustration in the aldolase structure which results in weaker native contacts in these frustrated regions. The predictive success of the B model also reveals the potential use of B factor information for energetic weighting in general protein modeling.