Non-covalent biological polymers play important roles in cellular function and disease. These include chromatin, a protein-DNA polymer that represents the functional form of the genome, and amyloid fibrils, protein-protein assemblies often associated with neurodegenerative disorders. Unraveling the forces and interactions that define the structure and function of such polymers is still a tremendous challenge for structural biology as it requires the ability to span many length and time scales, and the capability to construct relevant samples that represent the complexity, dynamics and multivalency of functional biological entities. In the first part of this presentation, I will describe spectroscopic approaches based on solid-state NMR that were used to determine the atomic-resolution structure of a model amyloid fibril. This structure provides a basis for understanding amyloid fibril heterogeneity and their extraordinary thermodynamic stability, characteristics with important implications in disease. In the second part, I will present a chemical biology toolbox that allows the efficient construction of chemically well-defined designer chromatin arrays. Combined with H/D exchange, NMR, and fluorescence-based experiments, these synthetic polymers enabled the investigation of chromatin structure and dynamics as a function of post-translational modifications such as ubiquitin. Our results suggest novel mechanisms of chromatin polymer decompaction, with important implications for gene regulation and access to genetic information in the cell.

Galia Debelouchina (Princeton University)