Department of Integrative Structural and Computational Biology, Scripps Research Institute , La Jolla, California 92037, United States.
Molecular Structure and Function Program, Hospital for Sick Children , Toronto, Ontario M5G 0A4, Canada.
J Am Chem Soc. 2016 Aug 10;138(31):9730-42. doi: 10.1021/jacs.6b06543. Epub 2016 Jul 19.
The traditional structure-function paradigm has provided significant insights for well-folded proteins in which structures can be easily and rapidly revealed by X-ray crystallography beamlines. However, approximately one-third of the human proteome is comprised of intrinsically disordered proteins and regions (IDPs/IDRs) that do not adopt a dominant well-folded structure, and therefore remain "unseen" by traditional structural biology methods. This Perspective considers the challenges raised by the "Dark Proteome", in which determining the diverse conformational substates of IDPs in their free states, in encounter complexes of bound states, and in complexes retaining significant disorder requires an unprecedented level of integration of multiple and complementary solution-based experiments that are analyzed with state-of-the art molecular simulation, Bayesian probabilistic models, and high-throughput computation. We envision how these diverse experimental and computational tools can work together through formation of a "computational beamline" that will allow key functional features to be identified in IDP structural ensembles.
传统的结构-功能范式为结构可以通过 X 射线晶体学光束线轻松快速揭示的折叠良好的蛋白质提供了重要的见解。然而，人类蛋白质组的大约三分之一由固有无序的蛋白质和区域（IDPs/IDRs）组成，这些蛋白质和区域不采用占主导地位的折叠良好的结构，因此仍然被传统的结构生物学方法“看不见”。本文从“暗蛋白质组”（Dark Proteome）的角度考虑了所提出的挑战，其中确定 IDP 在自由状态、结合状态的遭遇复合物以及保留显著无序的复合物中的多种构象亚稳态需要前所未有的整合多种互补的基于溶液的实验，这些实验与最先进的分子模拟、贝叶斯概率模型和高通量计算相结合进行分析。我们设想这些不同的实验和计算工具如何通过形成“计算光束线”来协同工作，从而可以在 IDP 结构集合中识别关键功能特征。
