Structure-based prediction of domain-peptide binding affinity by dissecting residue interaction profile at complex interface: a case study on CAL PDZ domain.
Structure-based prediction of domain-peptide binding affinity by dissecting residue interaction profile at complex interface: a case study on CAL PDZ domain.
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DOI：
10.2174/09298665113209990039
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发表时间：
2013
影响因子：
1.6
通讯作者：
Rongzhong Jin;Yili Ma;L. Qin;Zhong Ni
中科院分区：
文献类型：
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作者：
Rongzhong Jin;Yili Ma;L. Qin;Zhong Ni
许多与细胞信号网络和翻译后修饰事件有关的重要蛋白质相互作用是由一个蛋白质中的球状结构域与另一个蛋白质中的短肽段结合所介导的。在目前的研究中，我们描述了一个结构级别的协议，以实现对此类相互作用中弱亲和力的定量预测。该方法以CAL PDZ结构域与CFTRC-末端模拟多肽的晶体结构为模板，构建了其他同类结构域-多肽复合体结构模型。随后，利用偏最小二乘法(PLS)和随机森林法(RF)计算了构建的复合体中结构域与多肽之间的独立残基对相互作用，并与实验测量的80个CAL PDZ结合体的亲和力进行了关联。我们证明：(A)非线性RF在模拟和预测结构域-肽相互作用的结合亲和力方面比线性偏最小二乘法更耗时，(B)所提出的基于结构的策略在捕捉结构域与肽的结合行为和相互作用信息方面比传统的基于序列的方法更有效和准确，(C)只有非常少的复杂界面上的残基对对结构域-肽结合有显著贡献。
Many important protein interactions related to cell signaling networks and post-translational modification events are mediated by the binding of a globular domain in one protein to a short peptide stretch in another. In the current study, we describe a structure-level protocol to realize the quantitative prediction of weak affinity in such interactions. This method uses the crystal structure of CAL PDZ domain complexed with a CFTR C-terminus mimic peptide as the template to construct other congeneric domain-peptide complex structure models. Subsequently, independent residue-pair interactions between the domain and peptide in constructed complexes are computed and correlated with experimentally measured affinity of 80 CAL PDZ binders by using partial least squares (PLS) and random forest (RF). We demonstrate that (a) the nonlinear RF is time-consuming but performs much well as compared to linear PLS in modeling and predicting the binding affinity of domain-peptide interactions, (b) the proposed structure-based strategy is more effective and accurate than those of traditional sequence-based methods in capturing the binding behavior and interaction information of domain with peptide, and (c) only very few residue-pairs at complex interface contribute significantly to domain-peptide binding.