Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy.
Center for Life Nano & Neuro Science, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy.
Sci Rep. 2023 Jun 23;13(1):10207. doi: 10.1038/s41598-023-37130-z.
Understanding the mechanisms driving bio-molecules binding and determining the resulting complexes' stability is fundamental for the prediction of binding regions, which is the starting point for drug-ability and design. Characteristics like the preferentially hydrophobic composition of the binding interfaces, the role of van der Waals interactions, and the consequent shape complementarity between the interacting molecular surfaces are well established. However, no consensus has yet been reached on the role of electrostatic. Here, we perform extensive analyses on a large dataset of protein complexes for which both experimental binding affinity and pH data were available. Probing the amino acid composition, the disposition of the charges, and the electrostatic potential they generated on the protein molecular surfaces, we found that (i) although different classes of dimers do not present marked differences in the amino acid composition and charges disposition in the binding region, (ii) homodimers with identical binding region show higher electrostatic compatibility with respect to both homodimers with non-identical binding region and heterodimers. Interestingly, (iii) shape and electrostatic complementarity, for patches defined on short-range interactions, behave oppositely when one stratifies the complexes by their binding affinity: complexes with higher binding affinity present high values of shape complementarity (the role of the Lennard-Jones potential predominates) while electrostatic tends to be randomly distributed. Conversely, complexes with low values of binding affinity exploit Coulombic complementarity to acquire specificity, suggesting that electrostatic complementarity may play a greater role in transient (or less stable) complexes. In light of these results, (iv) we provide a novel, fast, and efficient method, based on the 2D Zernike polynomial formalism, to measure electrostatic complementarity without the need of knowing the complex structure. Expanding the electrostatic potential on a basis of 2D orthogonal polynomials, we can discriminate between transient and permanent protein complexes with an AUC of the ROC of [Formula: see text] 0.8. Ultimately, our work helps shedding light on the non-trivial relationship between the hydrophobic and electrostatic contributions in the binding interfaces, thus favoring the development of new predictive methods for binding affinity characterization.
理解生物分子结合的机制并确定所得复合物的稳定性对于预测结合区域至关重要，因为这是药物能力和设计的起点。结合界面优先具有疏水性组成、范德华相互作用的作用以及相互作用分子表面之间的形状互补性等特征已得到充分证实。然而，对于静电作用的作用还没有达成共识。在这里，我们对具有实验结合亲和力和 pH 值数据的大量蛋白质复合物数据集进行了广泛的分析。探测氨基酸组成、电荷的分布以及它们在蛋白质分子表面上产生的静电势，我们发现：（i）尽管不同类别的二聚体在结合区域的氨基酸组成和电荷分布上没有明显差异，但（ii）具有相同结合区域的同源二聚体相对于具有非相同结合区域的同源二聚体和异源二聚体具有更高的静电兼容性。有趣的是，（iii）当根据结合亲和力对复合物进行分层时，对于基于短程相互作用定义的斑块，形状和静电互补性表现出相反的行为：具有较高结合亲和力的复合物具有较高的形状互补性值（伦纳德-琼斯势的作用占主导地位），而静电则随机分布。相反，具有低结合亲和力的复合物利用库仑互补性来获得特异性，这表明静电互补性可能在瞬态（或不太稳定）复合物中发挥更大的作用。鉴于这些结果，（iv）我们提供了一种新颖、快速且高效的方法，该方法基于二维 Zernike 多项式形式主义，无需知道复合物结构即可测量静电互补性。通过将静电势能扩展到二维正交多项式的基础上，我们可以用 AUC 的 ROC 来区分瞬态和稳定的蛋白质复合物[公式：见正文]0.8。最终，我们的工作有助于阐明结合界面中疏水性和静电贡献之间的复杂关系，从而有利于开发新的结合亲和力预测方法。
