Chemical Biology as an Engineering Framework for Next-Generation Biomaterials

Abstract

Chemical biology-based frameworks integrate principles from chemistry and biology to develop a better understanding of and better control over biological systems. Advances in this space have revolutionized how pharmaceutical companies develop new therapeutics, or how basic researchers investigate the minute aberrances that cause disease. Chemical biology enables such directions because it imparts modularity and (re)configurability into what has historically been a descriptive science. In this thesis, I report the development of a semi-synthetic protein functionalization and purification scheme through atypically split inteins. The method allows the installation of virtually any synthetic cargo on the N-terminus of proteins-of-interest in a single step. Second, I introduce a novel framework for the engineering of an exhaustive set of 17 distinct YES/AND/OR logical operators, with three orthogonal proteases as input. By genetically encoding these topologies rather than synthetically assembling them, we can rapidly engineer bespoke architectures that correspond to sophisticated logical operators. This autonomous molecular compilation-based approach holds promise in applications such as controlled release and biosensing. Third, I demonstrate an extension of the approach’s applicability beyond model protein cargos by applying logical operators to a diverse class of proteins that span different functional categories. I also lay the groundwork for a diversified set of inputs that can be genetically encoded into our bespoke topologies. These advances showcase the promise of chemical biology as a highly enabling engineering framework for the synthesis and user-directed modification of next-generation biomaterials endowed with true biocomputational promise.