Protein‐protein interactions are critical to protein function, but three‐dimensional (3D) arrangements of interacting proteins have proven hard to predict, even given the identities and 3D structures of the interacting partners. Specifically, identifying the relevant pairwise interaction surfaces remains difficult, often relying on shape complementarity with molecular docking while accounting for molecular motions to optimize rigid 3D translations and rotations. However, such approaches can be computationally expensive, and faster, less accurate approximations may prove useful for large‐scale prediction and assembly of 3D structures of multi‐protein complexes. We asked if a reduced representation of protein geometry retains enough information about molecular properties to predict pairwise protein interaction interfaces that are tolerant of limited structural rearrangements. Here, we describe a reduced representation of 3D protein accessible surfaces on which molecular properties such as charge, hydrophobicity, and evolutionary rate can be easily mapped, implemented in the MorphProt package. Pairs of surfaces are compared to rapidly assess partner‐specific potential surface complementarity. On two available benchmarks of 185 overall known protein complexes, we observe predictions comparable to other structure‐based tools at correctly identifying protein interaction surfaces. Furthermore, we examined the effect of molecular motion through normal mode simulation on a benchmark receptor‐ligand pair and observed no marked loss of predictive accuracy for distortions of up to 6 Å Cα‐RMSD. Thus, a shape reduction of protein surfaces retains considerable information about surface complementarity, offers enhanced speed of comparison relative to more complex geometric representations, and exhibits tolerance to conformational changes.

中文翻译：

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蛋白质结构的简化几何表示确定互补的相互作用界面


蛋白质-蛋白质相互作用对于蛋白质功能至关重要，但事实证明，即使考虑到相互作用伙伴的身份和 3D 结构，相互作用蛋白质的三维 (3D) 排列也难以预测。具体来说，识别相关的成对相互作用表面仍然很困难，通常依赖于分子对接的形状互补性，同时考虑分子运动以优化刚性 3D 平移和旋转。然而，这种方法的计算成本可能很高，而且速度更快、精度较低的近似可能对大规模预测和多蛋白复合物 3D 结构的组装有用。我们询问蛋白质几何形状的简化表示是否保留了有关分子特性的足够信息来预测能够容忍有限结构重排的成对蛋白质相互作用界面。在这里，我们描述了 3D 蛋白质可访问表面的简化表示，在该表面上可以轻松映射电荷、疏水性和进化速率等分子特性，并在 MorphProt 包中实现。比较表面对以快速评估合作伙伴特定的潜在表面互补性。在 185 个已知蛋白质复合物的两个可用基准上，我们观察到与其他基于结构的工具在正确识别蛋白质相互作用表面方面的预测相当。此外，我们通过正常模式模拟对基准受体-配体对检查了分子运动的影响，并观察到对于高达 6 Å Cα-RMSD 的畸变，预测准确性没有明显损失。 因此，蛋白质表面的形状减小保留了关于表面互补性的大量信息，提供了相对于更复杂的几何表示的更快的比较速度，并且表现出对构象变化的耐受性。