Microstructural Organization in α-Synuclein Solutions
Microstructural Organization in α-Synuclein Solutions
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DOI：
10.1021/acs.macromol.1c02550
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发表时间：
2022-03-31
期刊：
影响因子：
5.5
通讯作者：
Muthukumar, Murugappan
中科院分区：
文献类型：
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作者：
Das, Shibananda;Muthukumar, Murugappan
我们研究了本质上无序的蛋白质α-突触核蛋白在溶液中的结构演变，它是蛋白质浓度和加盐浓度的函数。考虑到基于蛋白质序列的静电和排除的体积相互作用，我们的朗之万动力学模拟表明，α-突触核蛋白分子组装成聚集体和渗流结构，自发选择了具有微相分离特征的主导结构。这种微相组装主要是由蛋白质分子N端和C端残基之间的静电相互作用驱动的，盐的存在松散了微结构的致密性。我们用链间径向分布函数和实验上可测量的残基间接触图和静态结构因子来量化自发形成的微结构的特征。我们的结果与通常假设的液液相分离(LLP)在本质上无序的蛋白质溶液中形成液滴的机制相反，为理解无膜细胞器的诞生和结构开辟了新的范式。一般来说，构建内在无序的蛋白质和其他生物大分子体系的相图需要将微观相分离的特征融入到其他大相分离和渗流机制中。
We have investigated the structural evolution in solutions of the intrinsically disordered protein, alpha-synuclein, as a function of protein concentration and added salt concentration. Accounting for electrostatic and excluded volume interactions based on the protein sequence, our Langevin dynamics simulations reveal that alpha-synuclein molecules assemble into aggregates and percolated structures with a spontaneous selection of a dominant structure characteristic of microphase separation. This microphase assembly is mainly driven by electrostatic interactions between the residues in N-terminal and C-terminal of the protein molecules, and presence of salt loosens the compactness of the microstructures. We have quantified the features of the spontaneously formed microstructures using interchain radial distribution functions, and experimentally measurable inter-residue contact maps and static structure factors. Our results are in contrast to the commonly hypothesized mechanism of liquid-liquid phase separation (LLPS) for the formation of droplets in solutions of intrinsically disordered proteins, opening a new paradigm to understand the birth and structure of membraneless organelles. In general, construction of phase diagrams of intrinsically disordered proteins and other biomacromolecular systems needs to incorporate features of microphase separation into other mechanisms of macrophase separation and percolation.