Zhang, Yao
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Publication Exploring the World of Helix Association: Disease Mechanism, Basic Folding and Novel Design(2011-08-12) Zhang, YaoHelix association provides an efficient model for studying the fundamental principles behind protein folding. It also serves as a suitable template for the design of proteins with novel functions. This thesis begins by investigating the role of transmembrane helix association in protein folding, where a novel “protein-folding-centric” viral fusion model has been proposed here to explain the membrane-fusion process of paramyxovirus. Furthermore, the forces driving membrane helix association, which determine both affinity and orientation, have been quantitatively studied using a model membrane peptide MS1. Finally, two examples are discussed that illustrate the application of helix association in novel protein design. A pH-switchable drug delivery system for the endosomal escape of biomacromolecular therapeutics has been designed using the helix-association model. The sequence is designed to form a stable water-soluble helix bundle at pH 7.4 and to insert in membrane at lower pH to promote endosomal escape. The most successful sequence shows selective release for biomacromolecule (ATP and miRNA) at lower pH (pH 5.4). The assembly of the designed peptide has been studied in aqueous buffer, detergent micelle and model lipid bilayer using the most successful sequence. Also, the paradigm of helix association has been applied to the design of a membrane metalloprotein, which can serve as a template for further design of membrane metalloenzymes. In summary, the work in this thesis has established an efficient model for helix association that can be used to solve problems in both basic and applied research.