NSF-ANR: Cellular Crowding and Condensation Under Shear Flow

生物细胞内部是高度浓缩的生物分子、蛋白质和核酸的混合物，它们经常相互作用。这些相互作用大多是非特异性的，但它们可能导致聚类、聚集和相分离区域的形成，所有这些都可能对生物学功能产生重大影响。在这个项目中，活细胞内的流体动力学流动被作为一个新的维度来研究，它有望调节瞬时分子相互作用，从而增强或抑制聚集和相分离。这些努力的结果是对生物分子如何在密集的生物环境中相互作用的更完整、完全动态的看法。该项目涉及生物物理实验和计算机模拟的紧密结合。美国和法国研究小组之间的国际合作，为在外部流动存在下的生物分子相互作用的大规模模拟开发互补的计算专业知识，具有协同效益。本科生和研究生广泛参与高度跨学科的研究，重点是继续招募和支持女性和代表性不足的少数民族从事生物物理研究，从而增强了研究活动的影响。开发针对生命科学专业的新物理课程是使物理教育与生物主题更加相关的另一个目标。在另一个方向上，开发了一个公共推广组件，其中物理演示与计算机模拟相结合，以说明在生物学背景下通过粒子相互作用扩散的抽象概念。在密集的细胞环境中，生物分子通过短暂的非特异性相互作用频繁地相互作用。这种相互作用可能导致聚类、凝结和聚集。在这里，剪切流对这些过程的影响被视为理解现实生物环境中生物分子行为的一个新维度。剪切流存在于生物细胞中，有望调节瞬时相互作用和冷凝，并可能促进聚集。不同的模型系统将通过实验和计算机模拟进行研究。模型系统包括球状蛋白的浓缩溶液，用于研究非凝聚的瞬态聚类，肽- rna混合物用于研究凝聚，以及高度动态的内在无序肽，用于研究拥挤和凝聚环境中的分子内和分子间扩散。实验涉及纳米尺度光谱学和微米尺度显微镜技术；计算机模拟强调一种高度多尺度的方法，以便在分子和细胞尺度之间架起桥梁。美国和法国团队之间的国际合作增加了在流体动力流动中模拟大规模生物分子系统的互补专业知识。本科生和研究生广泛参与高度跨学科的研究，重点是继续招募和支持女性和代表性不足的少数民族从事生物物理研究，从而增强了研究活动的影响。开发针对生命科学专业的新物理课程是使物理教育与生物主题更加相关的另一个目标。在另一个方向上，开发了一个公共推广组件，其中物理演示与计算机模拟相结合，以说明在生物学背景下通过粒子相互作用扩散的抽象概念。这个美国/法国合作项目由美国国家科学基金会和法国国家研究机构支持，其中美国国家科学基金会资助美国研究者，法国国家研究机构资助法国合作伙伴。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Inside biological cells there is a highly concentrated mix of biomolecules, proteins and nucleic acids, that interact frequently. Most of these interactions are non-specific, but they may nevertheless lead to clustering, aggregation, and the formation of phase separated regions, all of which can have a significant impact on biological function. In this project, hydrodynamic flow present inside living cells is studied as a new dimension that is expected to modulate transient molecular interactions and enhance or suppress aggregation and phase separation as a consequence. The outcome of these efforts is a more complete, fully dynamic view of how biomolecules interact in dense biological environments. The project involves a close integration between biophysical experiments and computer simulations. There are synergistic benefits from international collaboration between US and French groups to develop complementary computational expertise for large-scale simulations of interacting biomolecules in the presence of external flow. The impact of the research activities is enhanced by extensive involvement of undergraduate and graduate students in highly interdisciplinary research with a strong focus on the continued recruitment and support of females and underrepresented minorities in biophysical research. The development of a new physics curriculum targeted at life science majors is another goal for making physics education more relevant for biology topics. In another direction, a public outreach component is developed where physical demonstrations are combined with computer simulations to illustrate the abstract concept of diffusion via particle interactions in the context of biology. In dense cellular environments biomolecules interact frequently via transient non-specific interactions. Such interactions may lead to clustering, condensation, and aggregation. Here the effect of shear flow on such processes is examined as a new dimension towards understanding the behavior of biomolecules in realistic biological environments. Shear flow is present in biological cells and is expected to modulate transient interactions and condensation and potentially facilitate aggregation. Different model systems will be investigated via experiments and computer simulations. The model systems include concentrated solutions of globular proteins to study non-condensing transient clustering, peptide-RNA mixtures to study condensation, and highly dynamic intrinsically disordered peptides to examine intra- and intermolecular diffusion in crowded and condensing environments. Experiments involve nano-scale spectroscopy and micron-scale microscopy techniques; computer simulations emphasize a highly multi-scale approach in order to bridge between molecular and cellular scales. International collaboration between US and French groups adds complementary expertise for simulating large-scale biomolecular systems in the presence of hydrodynamic flow. The impact of the research activities is enhanced by extensive involvement of undergraduate and graduate students in highly interdisciplinary research with a strong focus on the continued recruitment and support of females and underrepresented minorities in biophysical research. The development of a new physics curriculum targeted at life science majors is another goal for making physics education more relevant for biology topics. In another direction, a public outreach component is developed where physical demonstrations are combined with computer simulations to illustrate the abstract concept of diffusion via particle interactions in the context of biology.This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.