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Investigating protein folding by the de novo design of an α-helix oligomer

Author

Jamie Phan, University of the Pacific

Date of Award

2013

Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)

Department

Chemistry

First Advisor

Jerry Tsai

First Committee Member

Charles McCallum

Second Committee Member

Geoffrey Lin-Cereghino

Abstract

Proteins are composed of a unique sequence of amino acids, whose order guides a protein to adopt its particular fold and perform a specific function. It has been shown that a protein's 3-dimensional structure is embedded within its primary sequence. The problem that remains elusive to biochemists is how a protein's primary sequence directs the folding to adopt such a specific conformation. In an attempt to gain a better understanding of protein folding, my research tests a novel model of protein packing using protein design. The model defines the knob-socket construct as the fundamental unit of packing within protein structure. The knob-socket model characterizes packing specificity in terms of amino acid preferences for sockets in different environments: sockets filled with a knob are involved in inter-helical interactions and free sockets are involved in intra-helical interactions. Equipped with this knowledge, I sought to design a unique protein, Ksα1.1, completely de novo. The sequence was selected to induce helix formation with a predefined tertiary packing interface. Circular dichroism showed that Ksα1.1 formed α-helical secondary structure as intended. The nuclear magnetic resonance studies demonstrated formation of a high order oligomer with increased protein concentration. These results and analysis prove that the knob-socket model is a predictive model for all α-helical protein packing. More importantly, the knob-socket model introduces a new protein design method that can potentially hold a solution to the folding problem.

Pages

92

Recommended Citation

Phan, Jamie. (2013). Investigating protein folding by the de novo design of an α-helix oligomer. University of the Pacific, Thesis - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/859