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Title: Design and biophysical analysis of a de novo protein library based on a novel α-helical topology
Authors: Yeung, Kevin
Advisors: Hecht, Michael H
Department: Chemical and Biological Engineering
Certificate Program: Engineering Biology Program
Class Year: 2023
Abstract: De novo protein design has been an important source of novel proteins and structures with promising biological activity highly applicable in chemistry and medicine. In recent years, computational design has relied on marked improvements made in structure prediction in order to construct hyperstable proteins on an atomic level of resolution. Here I describe the design and development of a combinatorial protein library based on a novel α-helical topology through binary patterning, the premise that residue hydrophobicity determines tertiary structure. I hypothesized that randomizing this protein’s hydrophobic core would generate a diverse collection of mutants with unique internal binding pockets and thus unique binding affinities for small molecules. Predictive algorithms suggest that a sample of the protein library may maintain the original tertiary structure, but may become less tightly packed upon randomization and thus harbor promising putative sites for ligand binding. A biophysical analysis of the same sample indicate that the de novo proteins are highly thermostable and structurally disordered. To assess the viability of this protein library for identifying protein candidates for ligand binding, I conducted a case study on dioxin, an anthropogenic toxin which cannot be degraded by natural means. My findings demonstrate that this novel protein library could be leveraged as a preliminary screening method for discovering new proteins.
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Chemical and Biological Engineering, 1931-2023

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