Centro de Biologia Molecular "Severo Ochoa" CSIC-UAM Cantoblanco, Madrid, Spain.
Bioinformatics. 2019 Dec 1;35(23):4971-4978. doi: 10.1093/bioinformatics/btz301.
Protein function is intrinsically linked to native dynamics, but the systematic characterization of functionally relevant dynamics remains elusive besides specific examples. Here we exhaustively characterize three types of dynamical couplings between protein residues: co-directionality (moving along collinear directions), coordination (small fluctuations of the interatomic distance) and deformation (the extent by which perturbations applied at one residue modify the local structure of the other one), which we analytically compute through the torsional network model.
We find that ligand binding sites are characterized by large within-site coordination and co-directionality, much larger than expected for generic sets of residues with equivalent sequence distances. In addition, catalytic sites are characterized by high coordination couplings with other residues in the protein, supporting the view that the overall protein structure facilitates the catalytic dynamics. The binding sites of allosteric effectors are characterized by comparably smaller coordination and higher within-site deformation than other ligands, which supports their dynamic nature. Allosteric inhibitors are coupled to the active site more frequently through deformation than through coordination, while the contrary holds for activators. We characterize the dynamical couplings of the sodium-dependent Leucine transporter protein (LeuT). The couplings between and within sites progress consistently along the transport cycle, providing a mechanistic description of the coupling between the uptake and release of ions and substrate, and they highlight qualitative differences between the wild-type and a mutant for which chloride is necessary for transport.
The program tnm is freely available at https://github.com/ugobas/tnm.
Supplementary data are available at Bioinformatics online.
蛋白质的功能与其固有动力学密切相关，但除了特定的例子之外，系统地描述与功能相关的动力学仍然难以捉摸。在这里，我们详尽地描述了蛋白质残基之间的三种类型的动力学耦合：共方向性（沿共线方向移动）、协调性（原子间距离的小波动）和变形性（在一个残基上施加的扰动改变另一个残基的局部结构的程度），我们通过扭转网络模型对其进行了分析计算。
我们发现配体结合位点的特征是大的局部协调性和共方向性，远远大于具有相同序列距离的通用残基集的预期值。此外，催化位点的特征是与蛋白质中其他残基的高协调性耦合，这支持了整体蛋白质结构促进催化动力学的观点。变构效应物的结合位点的协调性和变形性都比其他配体小，这支持了它们的动态性质。变构抑制剂通过变形与活性位点的耦合比通过协调更为频繁，而激活剂则相反。我们描述了钠依赖性亮氨酸转运蛋白（LeuT）的动力学耦合。沿转运循环，位点之间和位点内的耦合一致，为离子和底物摄取和释放之间的耦合提供了一种机制描述，并且它们突出了野生型和突变体之间的定性差异，对于突变体，氯离子对于转运是必需的。
tnm 程序可在 https://github.com/ugobas/tnm 上免费获得。
补充数据可在 Bioinformatics 在线获得。
