SWISH-X, an expanded approach to detect cryptic pockets in proteins and at protein-protein interfaces
SWISH-X, an expanded approach to detect cryptic pockets in proteins and at protein-protein interfaces
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SWISH-X，一种检测蛋白质中和蛋白质-蛋白质界面上的隐秘口袋的扩展方法
DOI：
10.1101/2023.11.03.565527
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Borsatto A
中科院分区：
文献类型：
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作者：
Borsatto A
蛋白质-蛋白质相互作用介导细胞中的大多数分子过程，为扩大已知的可药物靶点提供了重要的机会。不幸的是，由于这些交互表面通常是平坦且无特征的，并且经常随着复杂形式的变化而变化，因此针对这些交互可能具有挑战性。这种表面变化可能会揭示隐藏的（神秘的）可药物口袋。在这里，我们分析了一组具有隐秘口袋的特征良好的蛋白质-蛋白质相互作用，并研究了当前计算方法的预测能力。根据我们的观察，我们开发了一种新的计算策略 SWISH-X（SWISH Expanded），它将 SWISH 已建立的神秘口袋识别功能与 OPES MultiThermal 的快速温度范围探索相结合。 SWISH-X 能够可靠地识别蛋白质-蛋白质界面上的隐秘口袋，同时保留其揭示分离蛋白质（例如 TEM-1 β-内酰胺酶）中隐秘口袋的预测能力。
Protein–protein interactions mediate most molecular processes in the cell, offering a significant opportunity to expand the set of known druggable targets. Unfortunately, targeting these interactions can be challenging due to their typically flat and featureless interaction surfaces, which often change as the complex forms. Such surface changes may reveal hidden (cryptic) druggable pockets. Here, we analyze a set of well-characterized protein–protein interactions harboring cryptic pockets and investigate the predictive power of current computational methods. Based on our observations, we developed a new computational strategy, SWISH-X (SWISH Expanded), which combines the established cryptic pocket identification capabilities of SWISH with the rapid temperature range exploration of OPES MultiThermal. SWISH-X is able to reliably identify cryptic pockets at protein–protein interfaces while retaining its predictive power for revealing cryptic pockets in isolated proteins, such as TEM-1 β-lactamase.