预测杂聚物相互作用:无序蛋白质序列的去混合与超混合

IF 11.6 1区 物理与天体物理 Q1 PHYSICS, MULTIDISCIPLINARY Physical Review X Pub Date : 2024-07-18 DOI:10.1103/physrevx.14.031011
Kyosuke Adachi, Kyogo Kawaguchi
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引用次数: 0

摘要

细胞中含有多种凝集物,这些凝集物因其成分之间的异型相互作用而自发形成。尽管人们已经广泛研究了凝集物形成的蛋白质和无序区序列,但仍未阐明各成分之间的相互作用规则,而这种规则允许去混合,即多个凝集物共存。在这里,我们通过拟合从人类蛋白质无序区中抽取的 200 多个序列的分子动力学模拟结果,构建了异聚合物之间相互作用的有效理论。我们发现,两个异聚合物之间氨基酸对相互作用的总和可以很好地定性预测波义耳温度,而通过二聚体对近似,我们将序列中相邻氨基酸的影响纳入其中,可以定量地改进波义耳温度。改进后的理论与捕捉不同序列间有效相互作用强度的度量方法的发现相结合,可以在多组分模拟中选择多达三个相互混杂的无序区序列,以及生成与给定序列混杂的人工序列。由于我们确定的相互作用空间的低维性质,该理论指出了去混合或超混合的通用序列设计策略。作为相互作用空间几何论证的结果,我们发现,无论选择哪种粗粒度模型,能够相互去混合的不同序列的数量都受到强烈限制。总之,我们为估算异聚合物之间有效相互作用的方法构建了理论基础,这种方法可用于预测相分离特性以及无序蛋白质定位和功能的分配规则。
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Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences
Cells contain multiple condensates which spontaneously form due to the heterotypic interactions between their components. Although the proteins and disordered region sequences that are responsible for condensate formation have been extensively studied, the rule of interactions between the components that allow demixing, i.e., the coexistence of multiple condensates, is yet to be elucidated. Here, we construct an effective theory of the interaction between heteropolymers by fitting it to the molecular dynamics simulation results obtained for more than 200 sequences sampled from the disordered regions of human proteins. We find that the sum of amino acid pair interactions across two heteropolymers predicts the Boyle temperature qualitatively well, which can be quantitatively improved by the dimer pair approximation, where we incorporate the effect of neighboring amino acids in the sequences. The improved theory, combined with the finding of a metric that captures the effective interaction strength between distinct sequences, allowed the selection of up to three disordered region sequences that demix with each other in multicomponent simulations, as well as the generation of artificial sequences that demix with a given sequence. The theory points to a generic sequence design strategy to demix or hypermix thanks to the low-dimensional nature of the space of the interactions that we identify. As a consequence of the geometric arguments in the space of interactions, we find that the number of distinct sequences that can demix with each other is strongly constrained, irrespective of the choice of the coarse-grained model. Altogether, we construct a theoretical basis for methods to estimate the effective interaction between heteropolymers, which can be utilized in predicting phase separation properties as well as rules of assignment in the localization and functions of disordered proteins.
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来源期刊
Physical Review X
Physical Review X PHYSICS, MULTIDISCIPLINARY-
CiteScore
24.60
自引率
1.60%
发文量
197
审稿时长
3 months
期刊介绍: Physical Review X (PRX) stands as an exclusively online, fully open-access journal, emphasizing innovation, quality, and enduring impact in the scientific content it disseminates. Devoted to showcasing a curated selection of papers from pure, applied, and interdisciplinary physics, PRX aims to feature work with the potential to shape current and future research while leaving a lasting and profound impact in their respective fields. Encompassing the entire spectrum of physics subject areas, PRX places a special focus on groundbreaking interdisciplinary research with broad-reaching influence.
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