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标题：Integrating folding kinetics and protein function: Biphasic kinetics and dual binding specificity in a WW domain
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作者：John Karanicolas ; Charles L. Brooks
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：2004
卷号：101
期号：10
页码：3432-3437
DOI：10.1073/pnas.0304825101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Because of the association of {beta}-sheet formation with the initiation and propagation of amyloid diseases, model systems have been sought to further our understanding of this process. WW domains have been proposed as one such model system. Whereas the folding of the WW domains from human Yes-associated protein (YAP) and Pin have been shown to obey single-exponential kinetics, the folding of the WW domain from formin-binding protein (FBP) 28 has been shown to proceed via biphasic kinetics. From an analysis of free-energy landscapes from atomic-level molecular dynamics simulations, the biphasic folding kinetics observed in the FBP WW domain may be traced to the ability of this WW domain to adopt two slightly different forms of packing in its hydrophobic core. This conformational change is propagated along the peptide backbone and affects the position of a tryptophan residue shown in other WW domains to play a key role in binding. The WW domains of Pin and YAP do not support more than one type of packing each, leading to monophasic folding kinetics. The ability of the FBP WW domain to assume two different types of packing may, in turn, explain the capacity of this WW domain to bind two classes of ligand, a property that is not shared by other WW domains. These findings lead to the hypothesis that lability with respect to conformations separated by an observable barrier as a requirement for function is incompatible with the ability of a protein to fold via single-exponential kinetics.
关键词：protein folding ; β-sheet ; β-strand ; packing