Molecular underpinnings of elasticity and adhesion in self-assembling protein biopolymers

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The self-assembly of proteins and peptides is critical to many aspects of biology. Of increasing interest are large macromolecular assemblies that form in response to local solution conditions, such as protein-rich droplets (eg. tropoelastin, RNA binding proteins in membraneless organelles, mussel foot proteins), fibrous assemblies (eg. amyloid fibrils, silk, collagen), and disordered cross-linked materials (eg. elastin, resilin). The formation and function of each assemblage underlies fundamental biological processes, and also represents an opportunity to develop novel biomaterials with controlled assembly, functionality, and physical properties. To make full use of these systems it is first important to understand the principles that drive their assembly and structure, and which define their functional properties.*** We have used nuclear magnetic resonance (NMR) and extensive biophysical methods to elucidate the structures and assembly mechanisms of several types of self-assembling polypeptides: amyloid fibrils and cytotoxic oligomers; transmembrane helices; fluid droplets; and crosslinked materials based on human elastin. This has provided us with a robust set of tools for tracking the structure and dynamics of self-assembling peptides through their entire assembly process. Building on these previous studies, we will determine the molecular basis for the assembly and material properties of polypeptides exhibiting two specific properties of interest elasticity and surface adhesion. *** i. Determine the atomistic structures of resilin and resilin-based polypeptides. Resilin is an insect elastomer that differs significantly from vertebrate elastin in sequence (more polar and aromatic) and material properties (higher compressibility), and is poorly characterized at the molecular level. Structural characterization will provide insight into how resilin performs biomechanical functions in insects, and will be used to design resilin-based peptides with defined mechanical properties.*** ii. Determine the molecular basis for self-assembly and surface adhesion of mussel foot proteins. Mussel foot proteins (Mfps) are repetitive, disordered and highly chemically modified proteins which self-assemble to form strong underwater adhesives of unknown structure. We will determine the molecular basis for Mfp assembly and adhesion, and will test the utility of Mfps for surface attachment of elastic biomaterials.*** iii. Develop a molecular understanding of compression versus extension in protein elastomers. Using NMR methods we recently developed to monitor the molecular effects of elastic extension or compression on biopolymers, we will determine how resilin-based materials, which exhibit similar elastic moduli under both extension and compression, function as elastomers. This will provide important insights for both elastic tissue biology and biomaterials design.