电荷、$π$和疏水相互作用在内在无序蛋白序列依赖相分离中的作用比较
Comparative Roles of Charge, $π$ and Hydrophobic Interactions in Sequence-Dependent Phase Separation of Intrinsically Disordered Proteins
摘要：
为了建立一个可转移的、预测性的粗粒显式链模型来描述液液相分离（LLPS）过程中的生物分子凝聚体物，我们对DEAD盒解旋酶Ddx 4的N端固有无序区（IDR）进行了多链模拟，以评估静电、疏水、阳离子- $π$和芳香族相互作用在氨基酸序列依赖性LLPS中的作用。我们评估了3个残基-残基相互作用方案与共享的静电势。无论是一个共同的疏水性方案，也没有一个增强精氨酸/赖氨酸-芳香族阳离子- $π$相互作用始终占实验LLPS数据的野生型，电荷乱序，FtoA，和RtoK突变体的Ddx 4 IDR。相比之下，基于折叠球状蛋白结构之间的接触统计的相互作用再现了整体实验趋势，包括RtoK突变体具有大大降低的LLPS倾向。P-颗粒蛋白LAF-1的RtoK突变体的模拟和LLPS实验之间的一致性也被发现，强调在一定程度上，重要的LLPS驱动$π$相关的相互作用体现在经典的统计潜力。进一步的阐明将是必要的，但是，特别是苯丙氨酸的作用，在冷凝物组装，因为FtoA和YtoF突变体的实验表明，LLPS驱动苯丙氨酸相互作用显着弱于常见的统计电位所假定的。蛋白质-蛋白质静电相互作用由相对介电常数调制，相对介电常数取决于蛋白质浓度。分析理论表明，这种依赖性需要在凝聚相中增强蛋白质间的相互作用，但在稀相中更有利的蛋白质-溶剂相互作用。相反的趋势导致对LLPS的总体影响不大。
英文摘要：
Endeavoring toward a transferable, predictive coarse-grained explicit-chain model for biomolecular condensates underlain by liquid-liquid phase separation (LLPS), we conducted multiple-chain simulations of the N-terminal intrinsically disordered region (IDR) of DEAD-box helicase Ddx4, as a test case, to assess the roles of electrostatic, hydrophobic, cation-$π$, and aromatic interactions in amino acid sequence-dependent LLPS. We evaluated 3 residue-residue interaction schemes with a shared electrostatic potential. Neither a common hydrophobicity scheme nor one augmented with arginine/lysine-aromatic cation-$π$ interactions consistently accounted for the experimental LLPS data on the wildtype, a charge-scrambled, an FtoA, and an RtoK mutant of Ddx4 IDR. In contrast, interactions based on contact statistics among folded globular protein structures reproduce the overall experimental trend, including that the RtoK mutant has a much diminished LLPS propensity. Consistency between simulation and LLPS experiment was also found for RtoK mutants of P-granule protein LAF-1, underscoring that, to a degree, the important LLPS-driving $π$-related interactions are embodied in classical statistical potentials. Further elucidation will be necessary, however, especially of phenylalanine's role in condensate assembly because experiments on FtoA and YtoF mutants suggest that LLPS-driving phenylalanine interactions are significantly weaker than those posited by common statistical potentials. Protein-protein electrostatic interactions are modulated by relative permittivity, which depends on protein concentration. Analytical theory suggests that this dependence entails enhanced inter-protein interactions in the condensed phase but more favorable protein-solvent interactions in the dilute phase. The opposing trends lead to a modest overall impact on LLPS.
机构、总结、中文摘要均由AI分析而来，可能存在错误，请以论文正文为准。
