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Experimental evidence for a frustrated energy landscape in a three-helix-bundle protein family

机译：三螺旋束蛋白家族中受挫的能量格局的实验证据

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摘要

Energy landscape theory is a powerful tool for understanding the structure and dynamics of complex molecular systems, in particular biological macromolecules. The primary sequence of a protein defines its free-energy landscape and thus determines the folding pathway and the rate constants of folding and unfolding, as well as the protein's native structure. Theory has shown that roughness in the energy landscape will lead to slower folding1, but derivation of detailed experimental descriptions of this landscape is challenging. Simple folding models show that folding is significantly influenced by chain entropy; proteins in which the contacts are local fold quickly, owing to the low entropy cost of forming stabilizing, native contacts during folding. For some protein families, stability is also a determinant of folding rate constants. Where these simple metrics fail to predict folding behaviour, it is probable that there are features in the energy landscape that are unusual. Such general observations cannot explain the folding behaviour of the R15, R16 and R17 domains of a-spectrin. R15 folds ～3,000 times faster than its homologues, although they have similar structures, stabilities and, as far as can be determined, transition-state stabilities. Here we show that landscape roughness (internal friction) is responsible for the slower folding and unfolding of R16 and R17. We use chimaeric domains to demonstrate that this internal friction is a property of the core, and suggest that frustration in the landscape of the slow-folding spectrin domains may be due to misdock-ing of the long helices during folding. Theoretical studies have suggested that rugged landscapes will result in slower folding; here we show experimentally that such a phenomenon directly influences the folding kinetics of a 'normal' protein, that is, one with a significant energy barrier that folds on a relatively slow, millisecond-second, timescale.
机译：能量景观理论是了解复杂分子系统（尤其是生物大分子）的结构和动力学的有力工具。蛋白质的一级序列定义了其自由能态，因此决定了折叠途径以及折叠和展开的速率常数，以及蛋白质的天然结构。理论表明，能量分布中的粗糙度会导致折叠速度变慢1，但是对这种分布的详细实验说明的推导具有挑战性。简单的折叠模型表明，折叠受链熵的影响很大。由于在折叠过程中形成稳定的天然接触所需的信息熵费用较低，因此接触在其中局部折叠的蛋白质会快速折叠。对于某些蛋白质家族，稳定性也是折叠速率常数的决定因素。在这些简单的指标无法预测折叠行为的情况下，很可能能源格局中有一些不寻常的特征。这样的一般观察不能解释α-血影蛋白的R15，R16和R17结构域的折叠行为。尽管R15具有相似的结构，稳定性以及可以确定的过渡态稳定性，但它们的折叠速度比同系物快3,000倍。在这里，我们显示出景观粗糙度（内部摩擦）是R16和R17较慢的折叠和展开的原因。我们使用chimereric域来证明这种内部摩擦是核心的属性，并建议缓慢折叠的血影蛋白域的景观受挫可能是由于折叠过程中长螺旋的错接所致。理论研究表明，崎landscape的景观将导致折叠速度变慢。在这里，我们通过实验表明，这种现象直接影响“正常”蛋白质的折叠动力学，也就是说，这种蛋白质具有显着的能垒，可以在相对较慢的毫秒时间内折叠。

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  • 来源
    《Nature》 |2010年第7281期|685-688|共4页
  • 作者

    Beth G. Wensley; Sarah Batey; Fleur A. C. Bone; Zheng Ming Chan; Nuala R. Tumelty; Annette Steward; Lee Gyan Kwa; Alessandro Borgia; Jane Clarke;

  • 作者单位

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK Covagen AG, c/o ETH Zuerich, Y17 M22, Life Science ETH/Uni, Winterthurerstrasse 190, CH-8057 Zuerich, Switzerland;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK Biochemisches Institut, Universitaet Zuerich, Winterthurerstrasse 190, CH-8057 Zuerich, Switzerland;

    Department of Chemistry, University of Cambridge, MRC Centre for Protein Engineering, Lensfield Rd, Cambridge CB2 1EW UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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