Rational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potentially bind at desired regions of the interface of protein-protein complexes. The methodology is based on comparing the protein backbone structure of short peptide segments (epitopes) at the protein-protein interface with a collection of cyclic peptide backbone structures. A cyclic peptide that matches the backbone structure of the segment is used as a template for a binder by adapting the amino acid side chains to the side chains found in the target complex. For a small library of cyclic peptides with known high resolution structures we found for the majority (~82%) of 154 protein-protein complexes at least one very well fitting match for a cyclic peptide template to a protein-protein interface segment. The majority of the constructed protein-cyclic peptide complexes was very stable during Molecular Dynamics simulations and showed an interaction energy score that was typically more favorable compared to interaction scores of typical peptide-protein complexes. Our cPEPmatch approach could be a promising approach for rapid suggestion of cyclic peptide binders that could be tested experimentally and further improved by chemical modification.

合理设计蛋白质-蛋白质相互作用的特异性抑制剂对于控制细胞信号转导的药物设计以及研究蛋白质-蛋白质相互作用网络是理想的。我们已经开发出一种快速计算方法来合理设计可能在蛋白质-蛋白质复合物界面的所需区域结合的环状肽。该方法基于将蛋白质-蛋白质界面处的短肽段（表位）的蛋白质主链结构与环状肽主链结构的集合进行比较。通过使氨基酸侧链适应于靶复合物中发现的侧链，与片段的骨架结构匹配的环肽被用作结合物的模板。对于一个具有已知高分辨率结构的环状肽小文库，我们发现对于154种蛋白质-蛋白质复合物的大部分（〜82％），至少有一个非常合适的环肽模板与蛋白质-蛋白质界面区段的匹配。大多数构建的蛋白质-环状肽复合物在分子动力学模拟过程中非常稳定，并且与典型的肽-蛋白质复合物的相互作用分数相比，其相互作用能得分通常更为有利。我们的cPEPmatch方法可能是快速提出环肽结合剂的有前途的方法，可以通过实验进行测试并通过化学修饰进一步改进。大多数构建的蛋白质-环状肽复合物在分子动力学模拟过程中非常稳定，并且与典型的肽-蛋白质复合物的相互作用分数相比，其相互作用能得分通常更为有利。我们的cPEPmatch方法可能是快速提出环肽结合剂的有前途的方法，可以通过实验进行测试并通过化学修饰进一步改进。大多数构建的蛋白质-环状肽复合物在分子动力学模拟过程中非常稳定，并且与典型的肽-蛋白质复合物的相互作用分数相比，其相互作用能得分通常更为有利。我们的cPEPmatch方法可能是快速提出环肽结合剂的有前途的方法，可以通过实验进行测试并通过化学修饰进一步改进。