Fadda Elisa
Department of Chemistry, Maynooth University, Maynooth, Kildare, Ireland.
Proteins. 2015 Jul;83(7):1341-51. doi: 10.1002/prot.24825. Epub 2015 May 29.
Molecular recognition is a fundamental step in the coordination of biomolecular pathways. Understanding how recognition and binding occur between highly flexible protein domains is a complex task. The conformational selection theory provides an elegant rationalization of the recognition mechanism, especially valid in cases when unstructured protein regions are involved. The recognition of a poorly structured peptide, namely XPA67-80 , by its target receptor ERCC1, falls in this challenging study category. The microsecond molecular dynamics (MD) simulations, discussed in this work, show that the conformational propensity of the wild type XPA67-80 peptide in solution supports conformational selection as the key mechanism driving its molecular recognition by ERCC1. Moreover, all the mutations of the XPA67-80 peptide studied here cause a significant increase of its conformational disorder, relative to the wild type. Comparison to experimental data suggests that the loss of the recognized structural motifs at the microscopic time scale can contribute to the critical decrease in binding observed for one of the mutants, further substantiating the key role of conformational selection in recognition. Ultimately, because of the high sequence identity and analogy in binding, it is conceivable that the conclusions of this study on the XPA67-80 peptide also apply to the ERCC1-binding domain of the XPA protein.
分子识别是生物分子途径协调中的一个基本步骤。了解高度灵活的蛋白质结构域之间的识别和结合是如何发生的，是一项复杂的任务。构象选择理论为识别机制提供了一个优雅的合理化解释，尤其适用于涉及非结构化蛋白质区域的情况。对结构不佳的肽XPA67 - 80被其靶受体ERCC1的识别，就属于这一具有挑战性的研究类别。本文所讨论的微秒级分子动力学（MD）模拟表明，野生型XPA67 - 80肽在溶液中的构象倾向支持构象选择作为驱动其被ERCC1分子识别的关键机制。此外，本文研究的XPA67 - 80肽的所有突变相对于野生型都导致其构象无序显著增加。与实验数据的比较表明，在微观时间尺度上识别的结构基序的丧失可能导致其中一个突变体观察到的结合力的关键下降，进一步证实了构象选择在识别中的关键作用。最终，由于在结合方面具有高度的序列同一性和相似性，可以想象，这项关于XPA67 - 80肽的研究结论也适用于XPA蛋白的ERCC1结合域。
