Delaunay Maxence, Ha-Duong Tap
Université Paris-Saclay, CNRS, BioCIS, 17 avenue des Sciences, 91400 Orsay, France.
Université Paris-Saclay, CNRS, BioCIS, 17 avenue des Sciences, 91400 Orsay, France.
Biophys Chem. 2023 May;296:106987. doi: 10.1016/j.bpc.2023.106987. Epub 2023 Mar 4.
Many protein-protein interactions result from the binding of one folded protein with one short peptide segment, such as complexes formed by SH3 or PDZ domains. These transient protein-peptide interactions are notably involved in cellular signaling pathways and generally have low affinities, which opens the possibility to design competitive inhibitors of these complexes. We present and assess here our computational approach, called Des3PI, to design de novo cyclic peptides with potential high affinity for protein surfaces involved in interactions with peptide segments. The results were not conclusive for two receptors, the αVβ3 integrin and the CXCR4 chemokine receptor, but were promising in the case of SH3 and PDZ domains: For the former, Des3PI was able to find at least one cyclic sequence with six hotspots that binds a SH3 domain with a better theoretical affinity to the known proline-rich RLP2 peptide. For the latter, Des3PI could identify at least four cyclic sequences with four or five hotspots that have lower binding free energies computed by the MM-PBSA method than the reference peptide GKAP.
许多蛋白质-蛋白质相互作用是由一个折叠蛋白与一个短肽段结合产生的，例如由SH3或PDZ结构域形成的复合物。这些瞬时的蛋白质-肽相互作用显著参与细胞信号通路，且通常具有低亲和力，这为设计这些复合物的竞争性抑制剂提供了可能性。我们在此展示并评估我们的计算方法，称为Des3PI，用于从头设计对参与与肽段相互作用的蛋白质表面具有潜在高亲和力的环肽。对于αVβ3整合素和CXCR4趋化因子受体这两种受体，结果尚无定论，但对于SH3和PDZ结构域的情况则很有前景：对于前者，Des3PI能够找到至少一个具有六个热点的环序列，该序列与SH3结构域结合，其理论亲和力优于已知的富含脯氨酸的RLP2肽。对于后者，Des3PI能够识别至少四个具有四个或五个热点的环序列，通过MM-PBSA方法计算，这些序列的结合自由能低于参考肽GKAP。
