Kinetic Rate Constant Prediction Supports the Conformational Selection Mechanism of Protein Binding
Kinetic Rate Constant Prediction Supports the Conformational Selection Mechanism of Protein Binding
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DOI：
10.1371/journal.pcbi.1002351
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发表时间：
2012-01-01
影响因子：
4.3
通讯作者：
Bates, Paul A.
中科院分区：
文献类型：
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作者：
Moal, Iain H.;Bates, Paul A.
蛋白质-蛋白质动力学速率常数的预测为我们对分子识别的理解提供了一个基本的测试，并将在复杂生物系统的建模中发挥重要作用。在本文中，一个特征选择和回归算法适用于挖掘一个大的分子描述符，并构建简单的模型，使用经验数据的缔合和解离速率常数。使用单独的测试数据进行验证，可以组合预测的速率常数以计算结合亲和力，其准确度与现有技术经验自由能函数的准确度相匹配。该模型表明，协会的速率是线性相关的未结合的蛋白质的比例在结合的构象合奏相对于未结合的构象合奏，这表明结合伙伴必须采取的几何形状接近的绑定之前的绑定。这些模型反映了蛋白质结合的构象选择和群体转变机制，为该机制在蛋白质-蛋白质结合中的优势提供了强有力的单独证据，补充了结构和理论研究。
The prediction of protein-protein kinetic rate constants provides a fundamental test of our understanding of molecular recognition, and will play an important role in the modeling of complex biological systems. In this paper, a feature selection and regression algorithm is applied to mine a large set of molecular descriptors and construct simple models for association and dissociation rate constants using empirical data. Using separate test data for validation, the predicted rate constants can be combined to calculate binding affinity with accuracy matching that of state of the art empirical free energy functions. The models show that the rate of association is linearly related to the proportion of unbound proteins in the bound conformational ensemble relative to the unbound conformational ensemble, indicating that the binding partners must adopt a geometry near to that of the bound prior to binding. Mirroring the conformational selection and population shift mechanism of protein binding, the models provide a strong separate line of evidence for the preponderance of this mechanism in protein-protein binding, complementing structural and theoretical studies.