Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, One Brookings Drive, Campus Box 1097, St. Louis, MO 63130, USA.
Department of Biomedical Engineering and Center for Biological Systems Engineering, Washington University in St. Louis, One Brookings Drive, Campus Box 1097, St. Louis, MO 63130, USA.
J Mol Biol. 2018 Aug 3;430(16):2403-2421. doi: 10.1016/j.jmb.2018.05.012. Epub 2018 May 12.
Intrinsically disordered proteins and regions (IDPs/IDRs) are characterized by well-defined sequence-to-conformation relationships (SCRs). These relationships refer to the sequence-specific preferences for average sizes, shapes, residue-specific secondary structure propensities, and amplitudes of multiscale conformational fluctuations. SCRs are discerned from the sequence-specific conformational ensembles of IDPs. A vast majority of IDPs are actually tethered to folded domains (FDs). This raises the question of whether or not SCRs inferred for IDPs are applicable to IDRs tethered to FDs. Here, we use atomistic simulations based on a well-established forcefield paradigm and an enhanced sampling method to obtain comparative assessments of SCRs for 13 archetypal IDRs modeled as autonomous units, as C-terminal tails connected to FDs, and as linkers between pairs of FDs. Our studies uncover a set of general observations regarding context-independent versus context-dependent SCRs of IDRs. SCRs are minimally perturbed upon tethering to FDs if the IDRs are deficient in charged residues and for polyampholytic IDRs where the oppositely charged residues within the sequence of the IDR are separated into distinct blocks. In contrast, the interplay between IDRs and tethered FDs has a significant modulatory effect on SCRs if the IDRs have intermediate fractions of charged residues or if they have sequence-intrinsic conformational preferences for canonical random coils. Our findings suggest that IDRs with context-independent SCRs might be independent evolutionary modules, whereas IDRs with context-dependent SCRs might co-evolve with the FDs to which they are tethered.
无定形蛋白质和区域 (IDPs/IDRs) 的特征是具有明确的序列到构象关系 (SCRs)。这些关系是指对平均大小、形状、残基特异性二级结构倾向和多尺度构象波动幅度的序列特异性偏好。SCRs 是从 IDPs 的序列特异性构象集合中辨别出来的。绝大多数 IDPs 实际上都与折叠域 (FDs) 相连。这就提出了一个问题，即推断出的 IDPs 的 SCR 是否适用于与 FDs 相连的 IDRs。在这里，我们使用基于成熟力场范例和增强采样方法的原子模拟，对 13 个典型 IDRs 作为自主单元、作为连接到 FDs 的 C 末端尾巴以及作为 FDs 对之间的连接体进行建模，以获得 SCR 的比较评估。我们的研究揭示了关于 IDRs 的上下文独立和上下文相关 SCR 的一组一般观察结果。如果 IDRs 缺乏带电残基或对于序列内带相反电荷的残基被分成不同块的多两性 IDRs，则将其连接到 FDs 后，SCR 几乎不会受到干扰。相比之下，如果 IDRs 具有中间分数的带电残基，或者如果它们具有序列固有构象偏好的规范无规卷曲，则 IDRs 与连接的 FDs 之间的相互作用对 SCR 具有显著的调节作用。我们的发现表明，具有上下文独立 SCR 的 IDRs 可能是独立的进化模块，而具有上下文相关 SCR 的 IDRs 可能与它们连接的 FDs 共同进化。
