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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Separating the effects of internal friction and transition state energy to explain the slow frustrated folding of spectrin domains
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Separating the effects of internal friction and transition state energy to explain the slow frustrated folding of spectrin domains

机译：分离内部摩擦和过渡态能量的作用以解释光谱域缓慢而受挫的折叠

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摘要

The elongated three-helix bundle domains spectrin R16 and R17 fold some two to three orders of magnitude more slowly than their homologue R15. We have shown that this slow folding is due, at least in part, to roughness in the free-energy landscape of R16 and R17. We have proposed that this roughness is due to a frustrated search for the correct docking of partly preformed helices. However, this accounts for only a small part of the slowing of folding and unfolding. Five residues on the A helix of R15, when inserted together into R16 or R17, increase the folding rate constants, reduce landscape roughness, and alter the folding mechanism to one resembling R15. The effect of each of these mutations individually is investigated here. No one mutation causes the behavior seen for the five in combination. However, two mutations, E18F and K25V, significantly increase the folding and unfolding rates of both R16 and R17 but without a concomitant loss in landscape roughness. E18F has the greatest effect on the kinetics, and a Φ-value analysis of the C helix reveals that the folding mechanism is unchanged. For both E18F and K25V the removal of the charge and resultant transition state stabilization is the main origin of the faster folding. Consequently, the major cause of the unusually slow folding of R16 and R17 is the non-native burial of the two charged residues in the transition state. The slowing due to landscape roughness is only about fivefold.
机译：细长的三螺旋束结构域血影蛋白R16和R17比其同源物R15慢约2-3个数量级。我们已经表明，这种缓慢折叠至少部分是由于R16和R17的自由能态中的粗糙度。我们已经提出，这种粗糙度是由于对部分预形成的螺旋的正确对接的不便搜索所致。但是，这仅占折叠和展开速度减慢的一小部分。当将R15的A螺旋上的五个残基一起插入R16或R17中时，它们会增加折叠速率常数，降低景观粗糙度并将折叠机制更改为一个类似于R15的残基。此处分别研究了每种突变的影响。没有一种突变会导致五种组合的行为。但是，两个突变E18F和K25V显着提高了R16和R17的折叠和解折叠速率，但没有随之降低景观粗糙度。 E18F对动力学的影响最大，对C螺旋的Φ值分析表明折叠机制没有改变。对于E18F和K25V而言，电荷的去除和最终的过渡态稳定是快速折叠的主要来源。因此，R16和R17异常缓慢折叠的主要原因是两个处于过渡状态的带电残基的非天然埋葬。由于景观粗糙造成的减慢只有大约五倍。

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