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标题：Large-scale modulation of thermodynamic protein folding barriers linked to electrostatics
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作者：Øyvind Halskau ; Raul Perez-Jimenez ; Beatriz Ibarra-Molero 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：25
页码：8625-8630
DOI：10.1073/pnas.0709881105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Protein folding barriers, which range from zero to the tens of RT that result in classical two-state kinetics, are primarily determined by protein size and structural topology [Plaxco KW, Simons KT, Baker D (1998) J Mol Biol 277:985-994]. Here, we investigate the thermodynamic folding barriers of two relatively large proteins of the same size and topology: bovine {alpha}-lactalbumin (BLA) and hen-egg-white lysozyme (HEWL). From the analysis of differential scanning calorimetry experiments with the variable-barrier model [Munoz V, Sanchez-Ruiz JM (2004) Proc Natl Acad Sci USA 101:17646-17651] we obtain a high barrier for HEWL and a marginal folding barrier for BLA. These results demonstrate a remarkable tuning range of at least 30 kJ/mol (i.e., five to six orders of magnitude in population) within a unique protein scaffold. Experimental and theoretical analyses on these proteins indicate that the surprisingly small thermodynamic folding barrier of BLA arises from the stabilization of partially unfolded conformations by electrostatic interactions. Interestingly, there is clear reciprocity between the barrier height and the biological function of the two proteins, suggesting that the marginal barrier of BLA is a product of natural selection. Electrostatic surface interactions thus emerge as a mechanism for the modulation of folding barriers in response to special functional requirements within a given structural fold.
关键词：natural selection ; homologous proteins ; structural pK shifts ; conformational ensembles ; differential scanning calorimetry