Structural insights from beta-sandwich proteins inform the design of de novo immunoglobulin domains towards new age antibodies
Tamuka Chidyausiku (Author), David Baker (Degree supervisor)
Active sites and ligand-binding cavities in native proteins are often formed by curved [Beta] sheets, and the ability to control [Beta]-sheet curvature would allow design of binding proteins with cavities customized to specific ligands. Toward this end, we investigated the mechanisms controlling [Beta]-sheet curvature by studying the geometry of [Beta] sheets in naturally occurring protein structures and folding simulations and defined principles for design. We use these rules to de novo design jellyroll structures with double-stranded [Beta]- helices formed by eight antiparallel [Beta]-strands. The nuclear magnetic resonance structure of a hyper-thermostable design closely matched the computational model, demonstrating accurate control over the [Beta]-sheet structure and loop geometry. Our results open the door to the design of a broad range of non-local [Beta]-sheet protein structures like the immunoglobulines which among others are predominant in their role as antibodies
Thesis, Dissertation, English, 2019
[University of Washington Libraries], [Seattle], 2019