Beta-Sheet Peptide Assembly Beyond Sequence Patterning: Incorporation of Functional Domains, Computational Energy Minimization, and Assembly Pathway Selection
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Robang, Alicia Sze
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Abstract
We are interested in β-sheet peptide assembly for two reasons: 1) β-sheets are central to protein aggregation diseases, such as Alzheimer’s Disease, and 2) they are a design platform for therapeutic nanostructures. These reasons are connected – designing amino acid sequences to form specific structures reveals insights into possible β-sheet structures in diseases. Previous work has established that biological effects (e.g., therapeutic cellular stimulation or pathological toxicity) depend on structure (e.g., β-sheets can contain parallel or antiparallel β-strands). Furthermore, peptide aggregates can be polymorphic (inhomogeneous in molecular structure) and assemble into various nanostructures (e.g., nanofibers or oligomeric “nanoparticles,” which are aggregates of less than ~50 molecules). We seek to determine assembled β-sheet structures as a basis for predicting structures based on amino acid sequences, design amino acid sequences for assembly into specific structures, and understand relationships between structures and biological effects.
My thesis contributes to this field in two main ways: First, we applied structural biology to understand possible structures. Second, we implemented new methods for designing and characterizing β-sheet assemblies. In our structural biology efforts, we revealed the unexpected βsheet structures within Q11 peptide biomaterials, discovered a novel type of peptide coassembly, and identified challenges in incorporating functional domains into β-sheet self-assembling peptides, which can be detrimental to therapeutic applications. In designing new β-sheet peptides, we established a computational-experimental approach to form parallel or antiparallel β-sheets selectively. We also proposed an assembly pathway selection-based model inspired by structural measurements on a size-limited Aβ42 oligomer. Altogether, our work expands our understanding of potential structures in disease-related protein aggregation and inspires new routes for peptide-based biomaterial designs.
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2024-04-25
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Dissertation