Vargas-Rosales Pablo Andrés, Caflisch Amedeo
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
J Mol Biol. 2022 Sep 15;434(17):167661. doi: 10.1016/j.jmb.2022.167661. Epub 2022 May 28.
While being a thoroughly studied model of dynamic allostery in a small protein, the pathway of signal transduction in the PDZ3 domain has not been fully determined. Here, we investigate peptide binding to the PDZ3 domain by conventional and fully data-driven analyses of molecular dynamics simulations. First, we identify isoleucine 37 as a key residue by widely used computational procedures such as cross-correlation and community network analysis. Simulations of the Ile37Ala mutant show disruption of the coordinated movements of spatially close regular elements of secondary structure. Then, we employ a recently developed unsupervised, data-driven procedure to determine an optimized reaction coordinate (slowest-relaxation eigenvector) of peptide binding. We use this reaction coordinate to improve sampling by restarting additional simulations from the transition state region. Significant differences in the distributions of some of the pairwise residue distances in the bound and unbound states emerge from the projection onto the optimized reaction coordinate. The unsupervised analysis shows that allosteric signaling is transduced from the β2 strand, which forms part of the peptide binding site, to the spatially adjacent β3 and β4 strands, and from there to the α3 helix. The domino-like transmission of a (peptide binding) signal along β strands and α helices that are close in three-dimensional space is likely to be a general mechanism of allostery in single-domain proteins.
尽管作为一个在小蛋白中经过充分研究的动态别构模型，但PDZ3结构域中的信号转导途径尚未完全确定。在这里，我们通过对分子动力学模拟进行常规和完全数据驱动的分析，研究肽与PDZ3结构域的结合。首先，我们通过广泛使用的计算程序，如互相关和社区网络分析，将异亮氨酸37鉴定为关键残基。Ile37Ala突变体的模拟显示，空间上紧密的二级结构规则元件的协同运动受到破坏。然后，我们采用最近开发的无监督、数据驱动的程序来确定肽结合的优化反应坐标（最慢弛豫特征向量）。我们使用这个反应坐标，通过从过渡态区域重新启动额外的模拟来改进采样。将结合态和未结合态中一些成对残基距离的分布投影到优化反应坐标上，出现了显著差异。无监督分析表明，别构信号从构成肽结合位点一部分的β2链传导到空间相邻的β3和β4链，并从那里传导到α3螺旋。在三维空间中靠近的β链和α螺旋之间，（肽结合）信号的多米诺骨牌式传递可能是单结构域蛋白中别构的一般机制。
