Center for Life Nano and Neuro Science, Istituto Italiano di Tecnologia (IIT), Viale Regina Elena 291, 00161, Rome, Italy.
The Open University Affiliated Research Centre at Istituto Italiano di Tecnologia, Via Morego, 30, 16163, Genoa, Italy.
Sci Rep. 2022 Jul 15;12(1):12087. doi: 10.1038/s41598-022-16338-5.
What are the molecular determinants of protein-protein binding affinity and whether they are similar to those regulating fold stability are two major questions of molecular biology, whose answers bring important implications both from a theoretical and applicative point of view. Here, we analyze chemical and physical features on a large dataset of protein-protein complexes with reliable experimental binding affinity data and compare them with a set of monomeric proteins for which melting temperature data was available. In particular, we probed the spatial organization of protein (1) intramolecular and intermolecular interaction energies among residues, (2) amino acidic composition, and (3) their hydropathy features. Analyzing the interaction energies, we found that strong Coulombic interactions are preferentially associated with a high protein thermal stability, while strong intermolecular van der Waals energies correlate with stronger protein-protein binding affinity. Statistical analysis of amino acids abundances, exposed to the molecular surface and/or in interaction with the molecular partner, confirmed that hydrophobic residues present on the protein surfaces are preferentially located in the binding regions, while charged residues behave oppositely. Leveraging on the important role of van der Waals interface interactions in binding affinity, we focused on the molecular surfaces in the binding regions and evaluated their shape complementarity, decomposing the molecular patches in the 2D Zernike basis. For the first time, we quantified the correlation between local shape complementarity and binding affinity via the Zernike formalism. In addition, considering the solvent interactions via the residue hydropathy, we found that the hydrophobicity of the binding regions dictates their shape complementary as much as the correlation between van der Waals energy and binding affinity. In turn, these relationships pave the way to the fast and accurate prediction and design of optimal binding regions as the 2D Zernike formalism allows a rapid and superposition-free comparison between possible binding surfaces.
蛋白质-蛋白质结合亲和力的分子决定因素，以及它们是否与调节折叠稳定性的因素相似，是分子生物学的两个主要问题，其答案从理论和应用的角度都具有重要意义。在这里，我们分析了具有可靠实验结合亲和力数据的大量蛋白质-蛋白质复合物数据集和一组单体蛋白质的化学和物理特征，这些单体蛋白质的熔点数据可用。特别是，我们探测了蛋白质的空间组织：（1）残基之间的分子内和分子间相互作用能；（2）氨基酸组成；（3）它们的疏水性特征。分析相互作用能，我们发现强库仑相互作用优先与高蛋白质热稳定性相关，而强分子间范德华能与更强的蛋白质-蛋白质结合亲和力相关。对暴露于分子表面和/或与分子伴侣相互作用的氨基酸丰度的统计分析证实，位于蛋白质表面的疏水性残基优先位于结合区域，而带电荷的残基则相反。利用范德华界面相互作用在结合亲和力中的重要作用，我们专注于结合区域的分子表面，并评估它们的形状互补性，将分子斑块分解为二维 Zernike 基。我们首次通过 Zernike 形式主义量化了局部形状互补性和结合亲和力之间的相关性。此外，考虑到溶剂与残基疏水性的相互作用，我们发现结合区域的疏水性决定了它们的形状互补性，就像范德华能与结合亲和力之间的相关性一样。反过来，这些关系为快速准确地预测和设计最佳结合区域铺平了道路，因为二维 Zernike 形式主义允许在可能的结合表面之间进行快速且无需叠加的比较。
