The folding energy landscape and free energy excitations of cytochrome c.-猫眼课题宝

DOI：

10.1021/ar9002703

发表时间：

2010-05-18

期刊：

ACCOUNTS OF CHEMICAL RESEARCH

影响因子：

18.3

通讯作者：

中科院分区：

化学1区

文献类型：

作者：

Weinkam, Patrick;Zimmermann, Joerg;Romesberg, Floyd E.;Wolynes, Peter G.

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145804/?report=classic

共价结合的血红素辅因子在细胞色素c的折叠中起主导作用。由于血红素复杂的无机化学性质，有些人可能会认为细胞色素c的折叠是一个特殊的情况，它遵循的原则不同于那些用来描述没有辅因子的蛋白质折叠的原则。然而，最近的调查表明，通常用于描述许多蛋白质的折叠模型的工作以及细胞色素c时，血红素是明确介绍，并普遍提供的结果，同意与实验观察。我们将首先讨论基于简单的原生结构模型的结果。这些模型包括有吸引力的非相邻残基之间的相互作用，只有当它们存在于晶体结构中，在pH 7。由于有吸引力的非本地接触不包括在本地结构为基础的模型，他们的能量景观可以被描述为“完美的漏斗”。换句话说，基于天然结构的模型被能量引导朝向天然状态，并且不包含会阻碍折叠的能量陷阱。高能陷阱是导致特定的瞬态中间体被填充的挫折的来源。基于天然结构的模型确实包括由于排除体积而导致的残基之间的排斥。因此，如果不能跨越自身的链必须部分展开以进行折叠，那么非能量陷阱就可以存在。基于结构的天然模型捕获这些类型的运动的能力部分地是它们成功预测许多类型蛋白质的折叠途径的原因。没有挫折的模型很好地描述了从氢交换实验推断的细胞色素c折叠事件的序列，从而证明了它们作为起点的使用。在低pH值下，细胞色素c的折叠序列偏离pH 7时的折叠序列，并且偏离从具有完美漏斗能量景观的模型预测的折叠序列。交替折叠途径是“化学挫折”的结果。这种挫折的出现，因为蛋白质的某些区域是不稳定的比其他人由于可滴定的残基，在低pH值质子化的异质性分布。我们构建更复杂的模型，包括化学挫折，除了原生结构为基础的条款。这些更复杂的模型只是适度地扰乱了总体上仍然很好的能源格局。这些扰动模型可以准确地描述如何替代折叠途径在低pH值下使用。在碱性pH值，细胞色素c人口明显不同的结构合奏。例如，赖氨酸残基被去质子化并竞争血红素连接位点。可以描述在低pH下折叠的相同模型也可以很好地预测在碱性pH下填充的中间体的结构和相对稳定性。

The covalently bound heme cofactor plays a dominant role in the folding of cytochrome c. Due to the complicated inorganic chemistry of the heme, some might consider the folding of cytochrome c to be a special case that follows different principles than those used to describe folding of proteins without cofactors. Recent investigations, however, demonstrate that models which are commonly used to describe folding for many proteins work well for cytochrome c when heme is explicitly introduced and generally provide results that agree with experimental observations. We will first discuss results from simple native structure-based models. These models include attractive interactions between nonadjacent residues only if they are present in the crystal structure at pH 7. Since attractive nonnative contacts are not included in native structure-based models, their energy landscapes can be described as “perfectly funneled.” In other words, native structure-based models are energetically guided towards the native state and contain no energetic traps that would hinder folding. Energetic traps are sources of frustration which cause specific transient intermediates to be populated. Native structure-based models do include repulsion between residues due to excluded volume. Nonenergetic traps can therefore exist if the chain, which cannot cross over itself, must partially unfold in order for folding to proceed. The ability of native structure-based models to capture these type of motions is in part responsible for their successful predictions of folding pathways for many types of proteins. Models without frustration describe well the sequence of folding events for cytochrome c inferred from hydrogen exchange experiments thereby justifying their use as a starting point. At low pH, the folding sequence of cytochrome c deviates from that at pH 7 and from those predicted from models with perfectly funneled energy landscapes. Alternate folding pathways are a result of “chemical frustration.” This frustration arises because some regions of the protein are destabilized more than others due to the heterogeneous distribution of titratable residues that are protonated at low pH. We construct more complex models that include chemical frustration, in addition to the native structure-based terms. These more complex models only modestly perturb the energy landscape which remains overall well funneled. These perturbed models can accurately describe how alternative folding pathways are used at low pH. At alkaline pH, cytochrome c populates distinctly different structural ensembles. For instance, lysine residues are deprotonated and compete for the heme ligation site. The same models that can describe folding at low pH also predict well the structures and relative stabilities of intermediates populated at alkaline pH.