Deciphering Protein Folding Using Chemical Protein Synthesis

Abstract

Protein folding is a complex self-assembly process that enables a newly translated polypeptide to acquire the three-dimensional structure that defines its function. The mechanism of folding corresponds to the path on a funnel-shaped free energy landscape that the polypeptide traverses in order to reach the minimum that corresponds to a native tertiary structure or an ensemble of folded states. To understand protein folding means to characterize the folding transition state, intermediates, and thermodynamics and kinetics. Chemical protein synthesis is complementary to the available molecular biology and biophysical methods to study folding mechanisms. It enables precise modifications to polypeptide backbone and side chains, including single-atom substitutions, chiral editing, fine-tuning stereo-electronic interactions, artificial covalent linking, site-specific labeling with fluorophores, or incorporation of completely artificial building blocks. This chapter describes examples of the application of chemical approaches to the synthesis and modification of proteins in order to obtain unique insights into molecular determinants of protein folding.