We address the problem of triggering dissociation events between proteins that have formed a complex. We have collected a set of 25 non-redundant, functionally diverse protein complexes having high-resolution three-dimensional structures in both the unbound and bound forms. We unify elastic network models with perturbation response scanning (PRS) methodology as an efficient approach for predicting residues that have the propensity to trigger dissociation of an interacting protein pair, using the three-dimensional structures of the bound and unbound proteins as input. PRS reveals that while for a group of protein pairs, residues involved in the conformational shifts are confined to regions with large motions, there are others where they originate from parts of the protein unaffected structurally by binding. Strikingly, only a few of the complexes have interface residues responsible for dissociation. We find two main modes of response: In one mode, remote control of dissociation in which disruption of the electrostatic potential distribution along protein surfaces play the major role; in the alternative mode, mechanical control of dissociation by remote residues prevail. In the former, dissociation is triggered by changes in the local environment of the protein, e.g., pH or ionic strength, while in the latter, specific perturbations arriving at the controlling residues, e.g., via binding to a third interacting partner is required for decomplexation. We resolve the observations by relying on an electromechanical coupling model which reduces to the usual elastic network result in the limit of the lack of coupling. We validate the approach by illustrating the biological significance of top residues selected by PRS on select cases where we show that the residues whose perturbation leads to the observed conformational changes correspond to either functionally important or highly conserved residues in the complex.

我们解决了触发已形成复合物的蛋白质之间解离事件的问题。我们已经收集了25种非冗余，功能多样的蛋白质复合物，这些蛋白质复合物具有未结合和结合形式的高分辨率三维结构。我们使用扰动响应扫描（PRS）方法将弹性网络模型统一起来，作为一种有效的方法来预测残基，这些残基倾向于结合蛋白和未结合蛋白的三维结构，从而触发相互作用的蛋白对的解离。PRS揭示，对于一组蛋白质对而言，参与构象转换的残基被限制在运动较大的区域，而其他残基则源自蛋白质的部分结构不受结合的影响。惊人地 仅少数复合物具有负责解离的界面残基。我们发现两种主要的反应模式：在一种模式中，解离的远程控制在其中主要作用是沿着蛋白质表面的静电势分布的破坏。在替代模式中，主要是通过机械控制游离残基的解离。在前者中，解离是由蛋白质局部环境的变化（例如pH或离子强度）触发的，而在后者中，需要复杂的扰动到达控制残基（例如，通过与第三种相互作用的伴侣结合）来进行分解。我们依靠机电耦合模型解决了这些问题，该模型减少了通常的弹性网络，从而导致缺乏耦合的局限性。