Simple physical models connect theory and experiment in protein folding kinetics
Simple physical models connect theory and experiment in protein folding kinetics
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DOI：
10.1016/s0022-2836(02)00706-4
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发表时间：
2002-09-13
影响因子：
5.6
通讯作者：
Baker, D
中科院分区：
文献类型：
--
作者：
Alm, E;Morozov, AV;Baker, D
我们对蛋白质折叠问题背后的原理的理解可以通过开发和描述简单的模型来测试，这些模型做出的预测可以与实验数据进行比较。在这里，我们扩展了我们早期的折叠自由能景观模型，其中每个残基被认为要么像自然状态一样折叠，要么完全无序，通过研究代表氢键和主链扭转应变的额外因素的作用，并通过使用主方程方法和简单过渡态理论的混合来更详细地评估自由能势垒附近的运动学。对19个蛋白质的折叠PHI值的模型计算与实验数据进行了比较，对于其中一半以上的实验数据，相关系数在r=0.41到0.88之间；过渡态自由能垒的计算与37个单域蛋白质的测量速率相关(r=0.69)。该模型提供了可供选择的折叠途径的贡献，折叠景观的准平衡处理的有效性，以及蛋白质折叠的Arrhenius前因子的大小。最后，我们讨论了简单的基于自然状态的模型的局限性，并作为对这些模型的更一般的测试，为超过400个已知结构的小蛋白结构域的综合集合提供了折叠速度和机制的预测。(C)2002爱思唯尔科学有限公司。保留所有权利。
Our understanding of the principles underlying the protein-folding problem can be tested by developing and characterizing simple models that make predictions which can be compared to experimental data. Here we extend our earlier model of folding free energy landscapes, in which each residue is considered to be either folded as in the native state or completely disordered, by investigating the role of additional factors representing hydrogen bonding and backbone torsion strain, and by using a hybrid between the master equation approach and the simple transition state theory to evaluate kinelics near the free energy barrier in greater detail. Model calculations of folding phi-values are compared to experimental data for 19 proteins, and for more than half of these, experimental data are reproduced with correlation coefficients between r = 0.41 and 0.88; calculations of transition state free energy barriers correlate with rates measured for 37 single domain proteins (r = 0.69). The model provides insight into the contribution of alternative-folding pathways, the validity of quasi-equilibrium treatments of the folding landscape, and the magnitude of the Arrhenius prefactor for protein folding. Finally, we discuss the limitations of simple native-state-based models, and as a more general test of such models, provide predictions of folding rates and mechanisms for a comprehensive set of over 400 small protein domains of known structure. (C) 2002 Elsevier Science Ltd. All rights reserved.