This project is co-funded by the Chemical Mechanism, Function, and Properties Program, the Chemistry of Life Processes Program in the Chemistry Division, and the NSF Office of Advanced Cyberinfrastructure. In this project, Professor Zhongyue John Yang of the Department of Chemistry at Vanderbilt University is investigating the origins of wrapping chirality in lasso peptides, which are a class of knotted, interlocked molecules with growing promise in biotechnology and therapeutics. Although lasso peptides can theoretically form in either left- or right-handed wrapping configurations, nature has exclusively selected the right-handed form, a phenomenon that remains mechanistically unclear. This project combines cutting-edge high-throughput protein modeling and machine learning to uncover why this chiral preference exists and whether it can be re-engineered. Lasso peptides are ribosomally synthesized and post-translationally modified peptides that adopt a mechanically interlocked “lariat” shape. Despite the theoretical possibility of both left- and right-handed wrapping topologies (l-LaPs and r-LaPs), only right-handed forms have been identified in nature. This research investigates two hypotheses: (1) that r-LaPs are thermodynamically and kinetically preferred over l-LaPs, and (2) that lasso peptide cyclases selectively catalyze right-handed pre-lasso conformations. To evaluate these hypotheses, the project will develop high-throughput quantum mechanics (QM) and classical mo