DEPACT and PACMatch: A Workflow of Designing De Novo Protein Pockets to Bind Small Molecules
DEPACT and PACMatch: A Workflow of Designing De Novo Protein Pockets to Bind Small Molecules
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DEPACT 和 PACMatch：从头设计蛋白质袋以结合小分子的工作流程
DOI：
10.1021/acs.jcim.1c01398
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发表时间：
2022-02-28
影响因子：
5.6
通讯作者：
Liu, Haiyan
中科院分区：
文献类型：
--
作者：
Chen, Yaoxi;Chen, Quan;Liu, Haiyan
新功能蛋白质（如酶和生物传感器）的工程设计涉及设计用于小分子特异性结合的新蛋白质口袋。在这里，我们报告了两个新的计算方法来执行这项任务的工作流程。DEPACT（Design Pocket as a Cluster based on Templates）方法是一种数据驱动的方法，用于设计和评估作为孤立簇的小分子结合口袋，而PACMatch方法是一种计算方法，用于将簇模型中的口袋残基与给定蛋白质支架上的位置相匹配。使用DEPACT及其评分函数，可以设计具有天然口袋样化学组成和蛋白质-配体相互作用强度的口袋簇。DEPACT可以设计含有水或金属离子介导的蛋白质-配体相互作用的口袋簇。虽然能够有效地处理相对大的口袋簇模型（例如，PACMatch在恢复天然酶-底物复合物中口袋残基的天然位置的测试案例中优于以前的方法。
Engineering of new functional proteins such as enzymes and biosensors involves the design of new protein pockets for the specific binding of small molecules. Here, we report a workflow composed of two new computational methods to execute this task. The DEPACT (Design Pocket as a Cluster based on Templates) method is a data-driven approach to design and evaluate small-molecule-binding pockets as isolated clusters, while the PACMatch method is a computational approach to match pocket residues in a cluster model to positions on given protein scaffolds. Using DEPACT and its scoring function, pocket clusters of natural-pocket-like chemical compositions and protein-ligand interaction strength can be designed. DEPACT can design pocket clusters containing water- or metal-ion-mediated protein-ligand interactions. While being able to efficiently treat relatively large pocket cluster models (e.g., of around 10 pocket residues), PACMatch outperforms previous methods in test cases of recovering the native positions of pocket residues in natural enzyme-substrate complexes.