CAREER: Synthetic Protein Switches for Expanding the Folding Code

University Of South Carolina At Columbia, Columbia SC

Investigators

Abstract

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicholas Truex from the University of South Carolina to investigate a unique class of proteins, known as “protein switches”. Such proteins change their shape in response to small modifications to their amino acid sequence or changes in their environment. The ability of these proteins to change shape appears to play key roles in normal biological functions and diseases. This project will characterize synthetic protein switches with non-natural amino acids and designs to reveal the molecular principles of their behavior, which cannot be readily examined using natural proteins. In addition, the project will identify and characterize shape changing regions within eukaryotic proteins to expand our understanding of variations in the structures of natural proteins. The educational objective of the project is to provide graduate, undergraduate, and high school students with training in automated flow protein synthesis, physical biochemistry, spectroscopy, and molecular modeling. This project also includes a new outreach program, “Hidden Chemical Properties”, to excite K–12 students in STEM education and participation in the American Chemical Society Project SEED mentorship program to provide high school students with hands-on summer research experiences. This research project will systematically examine the molecular interactions that enable protein switches to adopt two distinct folded structures. By incorporating non-natural amino acids into protein switch designs, the study will dissect protein conformation and stability upon variations in side-chain interactions, hydrogen bonding, and electronic effects. Structural and energetic features will be characterized using experimental techniques, including circular dichroism, differential scanning calorimetry, NMR spectroscopy, and molecular modeling. The results will establish fundamental principles of protein folding and stability, enhance understanding of protein dynamics, and contribute new advances in protein design. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.