Center for Biological Physics, Arizona State University, Tempe, Arizona, United States of America.
PLoS Comput Biol. 2011 Oct;7(10):e1002154. doi: 10.1371/journal.pcbi.1002154. Epub 2011 Oct 6.
The allosteric mechanism plays a key role in cellular functions of several PDZ domain proteins (PDZs) and is directly linked to pharmaceutical applications; however, it is a challenge to elaborate the nature and extent of these allosteric interactions. One solution to this problem is to explore the dynamics of PDZs, which may provide insights about how intramolecular communication occurs within a single domain. Here, we develop an advancement of perturbation response scanning (PRS) that couples elastic network models with linear response theory (LRT) to predict key residues in allosteric transitions of the two most studied PDZs (PSD-95 PDZ3 domain and hPTP1E PDZ2 domain). With PRS, we first identify the residues that give the highest mean square fluctuation response upon perturbing the binding sites. Strikingly, we observe that the residues with the highest mean square fluctuation response agree with experimentally determined residues involved in allosteric transitions. Second, we construct the allosteric pathways by linking the residues giving the same directional response upon perturbation of the binding sites. The predicted intramolecular communication pathways reveal that PSD-95 and hPTP1E have different pathways through the dynamic coupling of different residue pairs. Moreover, our analysis provides a molecular understanding of experimentally observed hidden allostery of PSD-95. We show that removing the distal third alpha helix from the binding site alters the allosteric pathway and decreases the binding affinity. Overall, these results indicate that (i) dynamics plays a key role in allosteric regulations of PDZs, (ii) the local changes in the residue interactions can lead to significant changes in the dynamics of allosteric regulations, and (iii) this might be the mechanism that each PDZ uses to tailor their binding specificities regulation.
变构机制在几种 PDZ 结构域蛋白（PDZs）的细胞功能中起着关键作用，并且与药物应用直接相关；然而，详细阐述这些变构相互作用的性质和程度是一个挑战。解决这个问题的一个方法是探索 PDZ 的动力学，这可能提供关于分子内通讯如何在单个结构域内发生的见解。在这里，我们开发了一种改进的扰动响应扫描（PRS），该方法将弹性网络模型与线性响应理论（LRT）相结合，以预测两个研究最多的 PDZ（PSD-95 PDZ3 结构域和 hPTP1E PDZ2 结构域）变构跃迁中的关键残基。使用 PRS，我们首先确定在扰动结合位点时给出最高均方根波动响应的残基。引人注目的是，我们观察到具有最高均方根波动响应的残基与实验确定的涉及变构跃迁的残基一致。其次，我们通过连接在扰动结合位点时给出相同方向响应的残基来构建变构途径。预测的分子内通讯途径表明，PSD-95 和 hPTP1E 通过不同残基对的动态耦合具有不同的途径。此外，我们的分析提供了对 PSD-95 实验观察到的隐藏变构的分子理解。我们表明，从结合位点去除远端三分之一的α螺旋会改变变构途径并降低结合亲和力。总体而言，这些结果表明：（i）动力学在 PDZ 的变构调节中起着关键作用；（ii）残基相互作用的局部变化可能导致变构调节动力学的显著变化；（iii）这可能是每个 PDZ 用于调整其结合特异性调节的机制。
