Yu Feng, Sukenik Shahar
Quantitative Systems Biology Program, University of California, Merced, California, United States.
Department of Chemistry and Biochemistry, University of California, Merced, California, United States.
bioRxiv. 2023 Jan 21:2023.01.20.524980. doi: 10.1101/2023.01.20.524980.
Intrinsically disordered protein regions (IDRs) make up over 30% of the human proteome and instead of a native, well-folded structure exist in a dynamic conformational ensemble. Tethering IDRs to a surface (for example, the surface of a well-folded region of the same protein) can reduce the number of accessible conformations in IDR ensembles. This reduces the ensemble's conformational entropy, generating an effective entropic force that pulls away from the point of tethering. Recent experimental work has shown that this entropic force causes measurable, physiologically relevant changes to protein function, but how the magnitude of this force depends on the IDR sequence remains unexplored. Here we use all-atom simulations to analyze how structural preferences encoded in dozens of IDR ensembles contribute to the entropic force they exert upon tethering. We show that sequence-encoded structural preferences play an important role in determining the magnitude of this force and that compact, spherical ensembles generate an entropic force that can be several times higher than more extended ensembles. We further show that changes in the surrounding solution's chemistry can modulate IDR entropic force strength. We propose that the entropic force is a sequence-dependent, environmentally tunable property of terminal IDR sequences.
内在无序蛋白区域（IDRs）占人类蛋白质组的30%以上，它们不存在天然的、折叠良好的结构，而是以动态构象集合的形式存在。将IDRs连接到一个表面（例如，同一蛋白质的一个折叠良好区域的表面）可以减少IDR集合中可及构象的数量。这降低了集合的构象熵，产生一种有效的熵力，使其从连接点拉开。最近的实验工作表明，这种熵力会对蛋白质功能产生可测量的、生理上相关的变化，但这种力的大小如何取决于IDR序列仍未得到探索。在这里，我们使用全原子模拟来分析数十个IDR集合中编码的结构偏好如何对它们在连接时施加的熵力做出贡献。我们表明，序列编码的结构偏好在确定这种力的大小方面起着重要作用，并且紧凑的球形集合产生的熵力可能比更伸展的集合高出几倍。我们进一步表明，周围溶液化学性质的变化可以调节IDR熵力强度。我们提出，熵力是末端IDR序列的一种依赖于序列、可由环境调节的性质。
