Computational modelling of macromolecule interactions from droplets to cells

小体积的化学和物理过程几乎发生在日常生活的各个方面和生活本身。工业和家用喷雾剂中的人造气溶胶、大气气溶胶、纳米流体和微流体中的囊泡、乳液和细胞，都是发生不同化学反应的小体积例子。小体积的线性尺寸在纳米到几微米的范围内。研究人员试图在小体积中阐明各种化学物质如大分子、离子及其复合物的相互作用，一方面是为了了解生命的基本过程，另一方面是为了控制这些相互作用在技术上的应用。我的研究项目将通过计算方法专门研究蛋白质-蛋白质相互作用（PPIs）、大分子-离子相互作用、蛋白质-配体相互作用和大分子组装的稳定性和性质。蛋白质复合物中的原体、配体和组装中的大分子通过非共价相互作用结合。为了解剖大量非共价蛋白复合物中的PPIs，化学和结构生物学中使用了不同实验技术的组合，包括天然质谱（MS）， x射线晶体学，核磁共振波谱学，（冷冻）电子显微镜和计算方法。特别是，原生质谱现在普遍用于非共价生物组件的结构和热力学分析。我们计算的作用将是提供在实验中无法轻易检测到的ppi稳定性中缺失但关键的信息。为了理解二聚体中的ppi及其更大的组件，我们必须研究这个问题的几个方面。在我们的一个项目中，我们将研究蛋白质组件与表面碰撞的结果，以确定碎片模式，并从中确定PPIs的稳定性。本研究将为结合质谱技术的蛋白质组件的表面诱导解离实验提供指导原则。在我们理解PPIs的研究路径中，重要的是研究模拟细胞中膜和细胞器环境的拥挤环境中的组装途径。在液滴环境中的蛋白质配体研究将解决在药物发现领域使用质谱方法的重要基础问题。大分子-离子相互作用，如核酸-离子相互作用，在限制小体积将阐明限制在核酸周围的电荷分布的影响。因此，我的研究项目将涉及化学生物学、软物质和分析化学的前沿问题。

Chemical and physical processes in small volumes take place at almost every aspect of everyday life and in life itself. Man-made aerosols in industrial and household sprays, atmospheric aerosols, vesicles in nanofluidics and microfluidics, emulsions and cells, are prevalent examples of small volumes where distinct chemistry takes place. The small volumes have linear dimensions in the nanometer to a few micrometers range. Researchers try to elucidate the interactions of the various chemical species such as macromolecules, ions and their complexes in the small volumes in order to understand on the one hand fundamental process of life and on the other hand to control these interactions for applications in technology. My research program will specifically investigate the stability and nature of protein-protein interactions (PPIs), macromolecule-ion interactions, protein-ligand interactions and assemblies of macromolecules by using computational methods. The protomers in the protein complexes, the ligands, and the macromolecules in assemblies are bound by non-covalent interactions. To dissect PPIs in a vast array of non-covalent protein complexes, a combination of different experimental techniques have been used in chemistry and structural biology, which include native mass spectrometry (MS), X-ray crystallography,NMR spectroscopy, (cryo-)electron microscopy, and computational methods. In particular, native MS is now prevalent for structural and thermodynamic analyses of non-covalent biological assemblies. The role of our computations will be to provide missing but critical information in the stability of the PPIs that cannot be readily detected in experiments. To understand the PPIs in dimeric complexesand their larger assemblies we have to study several facets of the problem. In one of our projects we will investigate the outcome of collisions of protein assemblies with surfaces to determine the fragmentation pattern and from there the stability of PPIs. This study will provide guiding principles in surface-induced dissociation experiments of protein assemblies coupled to mass spectrometry techniques. In our research path for understanding the PPIs it is important to investigate assembly pathways in crowded environments that mimic the membrane and organelle environment in a cell. Protein-ligand studies in a droplet environment will address fundamental questions significant for the usage of mass spectrometry methods in the field of drug discovery. Macromolecule-ion interactions such as nucleic acid-ion interactions in confining small volumes will elucidate the effect of confinement in the charge distribution around a nucleic acid. My research program will thus address questions at the forefront of chemical biology, soft matter and analytical chemistry.