Molecular Binding Sites Are Located Near the Interface of Intrinsic Dynamics Domains (IDDs)

We provide evidence supporting that protein–protein and protein–ligand docking poses are functions of protein shape and intrinsic dynamics. Over sets of 68 protein–protein complexes and 240 nonhomologous enzymes, we recognize common predispositions for binding sites to have minimal vibrations and angular momenta, while two interacting proteins orient so as to maximize the angle between their rotation/bending axes (>65°). The findings are then used to define quantitative criteria to filter out docking decoys less likely to be the near-native poses; hence, the chances to find near-native hits can be doubled. With the novel approach to partition a protein into “domains” of robust but disparate intrinsic dynamics, 90% of catalytic residues in enzymes can be found within the first 50% of the residues closest to the interface of these dynamics domains. The results suggest an anisotropic rather than isotropic distribution of catalytic residues near the mass centers of enzymes.

本研究提供实验证据，证明蛋白质-蛋白质与蛋白质-配体的对接构象（docking poses）是蛋白质形状与固有动力学（intrinsic dynamics）的函数。针对68组蛋白质-蛋白质复合物和240个非同源酶的数据集，我们发现结合位点存在共同的倾向性：其振动与角动量均处于极低水平；同时两个相互作用的蛋白质会调整自身取向，使二者的旋转/弯曲轴之间的夹角最大化（大于65°）。基于上述发现，我们定义了量化筛选标准，用于过滤掉可能性较低的非天然对接诱饵（docking decoys）；借此可将找到近天然命中结果的概率提升一倍。通过将蛋白质划分为具有稳健但各异固有动力学的“动力学结构域”的全新方法，我们发现酶中90%的催化残基都位于距离这些动力学结构域界面最近的前50%残基范围内。研究结果表明，酶质量中心附近的催化残基呈各向异性分布，而非各向同性分布。