Computational modelling of macromolecule interactions from droplets to cells

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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 complexes***and 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.*****