LASSI: A lattice model for simulating phase transitions of multivalent proteins
LASSI: A lattice model for simulating phase transitions of multivalent proteins
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DOI：
10.1371/journal.pcbi.1007028
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发表时间：
2019-10-01
影响因子：
4.3
通讯作者：
Pappu, Rohit, V
中科院分区：
文献类型：
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作者：
Choi, Jeong-Mo;Dar, Furqan;Pappu, Rohit, V
分子物质的空间和时间组织是细胞超微结构的一个定义性标志，最近的注意力集中在无膜细胞器，也被称为生物分子凝聚物。感兴趣的是通过结合多价蛋白质和核酸分子的联合收割机相分离和网络的相变形成的缩合物。基于最近公认的缔合聚合物和多价蛋白质之间的类比，我们开发并部署了LASSI，这是一种开源计算引擎，可以计算多价蛋白质的特定结构相图。LASSI依赖于先验识别多价蛋白质内的贴纸和间隔区，并将贴纸映射到三维晶格上。一个蒙特卡洛引擎，结合了一套新的和建立的移动集，使模拟跟踪密度不均匀性和变化的程度，网络之间的贴纸作为蛋白质浓度和相互作用强度的函数。分布函数和其他顺序参数的计算，使我们能够计算完整的多价蛋白质的相图建模使用简单的立方晶格上的贴纸和间隔表示。这些计算使我们能够合理化实验观察，并为设计具有定制相行为的蛋白质结构打开了大门。LASSI可用于研究多组分体系的相行为，这使我们能够直接接触细胞生物分子凝聚体的物理原理。许多生物分子凝聚体通过多价蛋白质驱动的自发相变形成。这些分子是缔合聚合物的生物实例，其符合所谓的粘合剂和间隔物架构。所述粘着物是蛋白质-蛋白质或蛋白质-RNA相互作用基序和/或结构域，其可以彼此形成可逆的非共价交联。间隔物散布在贴纸之间，并且它们与溶剂分子的优先相互作用决定相变的协同性。在这里，我们报告了一个开源的计算引擎称为LASSI（LAttice仿真引擎的贴纸和间隔相互作用），使多组分系统的完整相图的计算包括粗粒度的多价蛋白质的表示。LASSI的目的是使计算有效的现象学建模的多组分混合物，包括多价蛋白质和RNA分子的自发相变。我们演示了应用LASSI使用模拟的线性和分支的多价蛋白质。我们表明，致密相最好描述为液滴跨越网络，其特征在于多价蛋白质之间的可逆物理交联。我们连接最近的观察，关于冷凝物的表观化学计量和停留时间之间的相关性，作为内部结构组织的代理，特别是内部密度的卷积和网络的范围内，冷凝物。最后，我们证明了饱和浓度阈值的概念不适用于专性异型相互作用驱动相变的多组分系统。这出现在多组分体系相图的椭球体结构中，它对体内生物分子凝聚物的调节有直接影响。
Author summary Spatial and temporal organization of molecular matter is a defining hallmark of cellular ultrastructure and recent attention has focused on membraneless organelles, which are also referred to as biomolecular condensates. Of interest are condensates that form via phase transitions that combine phase separation and networking of multivalent protein and nucleic acid molecules. Building on recently recognized analogies between associative polymers and multivalent proteins, we have developed and deployed LASSI, an open source computational engine that enables the calculation of architecture-specific phase diagrams for multivalent proteins. LASSI relies on a priori identification of stickers and spacers within a multivalent protein and mapping the stickers onto a 3-dimensional lattice. A Monte Carlo engine that incorporates a suite of novel and established move sets enables simulations that track density inhomogeneities and changes to the extent of networking among stickers as a function of protein concentration and interaction strengths. Calculation of distribution functions and other order parameters allow us to compute full phase diagrams for multivalent proteins modeled using a stickers-and-spacers representation on simple cubic lattices. These calculations allow us to rationalize experimental observations and open the door to the design of protein architectures with bespoke phase behavior. LASSI can be deployed to study the phase behavior of multicomponent systems, which allows us to make direct contact with the physical principles underlying cellular biomolecular condensates.Many biomolecular condensates form via spontaneous phase transitions that are driven by multivalent proteins. These molecules are biological instantiations of associative polymers that conform to a so-called stickers-and-spacers architecture. The stickers are protein-protein or protein-RNA interaction motifs and / or domains that can form reversible, non-covalent crosslinks with one another. Spacers are interspersed between stickers and their preferential interactions with solvent molecules determine the cooperativity of phase transitions. Here, we report the development of an open source computational engine known as LASSI (LAttice simulation engine for Sticker and Spacer Interactions) that enables the calculation of full phase diagrams for multicomponent systems comprising of coarse-grained representations of multivalent proteins. LASSI is designed to enable computationally efficient phenomenological modeling of spontaneous phase transitions of multicomponent mixtures comprising of multivalent proteins and RNA molecules. We demonstrate the application of LASSI using simulations of linear and branched multivalent proteins. We show that dense phases are best described as droplet-spanning networks that are characterized by reversible physical crosslinks among multivalent proteins. We connect recent observations regarding correlations between apparent stoichiometry and dwell times of condensates to being proxies for the internal structural organization, specifically the convolution of internal density and extent of networking, within condensates. Finally, we demonstrate that the concept of saturation concentration thresholds does not apply to multicomponent systems where obligate heterotypic interactions drive phase transitions. This emerges from the ellipsoidal structures of phase diagrams for multicomponent systems and it has direct implications for the regulation of biomolecular condensates in vivo.