Living cells have evolved sophisticated intracellular organization strategies that are challenging to reproduce synthetically. Biomolecular function depends on both structure and the properties of the surrounding medium. The ability to correlate structure to function at biologically relevant timescales, simulate the in vivo environment, and isolate biological networks for study in an artificial milieu represent engineering challenges with tremendous potential to impact both biological studies and biomedical applications.Efforts to understand biomolecular structure-function relationships have relied heavily on static structural depictions that do not fully describe the dynamic nature of reaction processes. This limitation is the result of difficulties in applying dynamic or time-resolved crystallographic methods to a majority of biomolecular targets. These challenges are associated with radiation damage and/or simultaneous and repetitive triggering of the biomolecular reaction within a crystal. X-ray transparent microfluidic platforms for protein crystallization can be used to address these challenges, enabling multi-crystal serial analysis strategies to avoid both radiation damage and the necessity of repeatedly cycling a reaction.  Such chips can also enable high throughput structural analysis with respect to many variables including pH and ionic strength to better understand biomolecule function.The challenge in designing synthetic organelles and in vivo microenvironments is maintaining crowding and compartmentalization while controlling the available intermolecular interactions.  Emerging experience has shown that complex coacervates (liquid-liquid phase separation) utilizing biomolecules produces an effective biomimetic microenvironment.  Initial efforts are focused on understanding how functionalities, introduced through sequence-specific motifs, affect biomolecule sequestration and function.  Molecular design enables the use of structure and microphase separation as additional design parameters. Using these strategies, I propose the development of artificial organelles for applications in biochemistry, bioenergetics, biocatalysis, and biomedicine. Insights gained from developing such systems may provide insight into the function of analogous membraneless organelles as well as potential pathways for the evolution of prebiotic life.

Biomimetic and microfluidic approaches to biomolecular function and application

246th National Meeting (2013)

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