Awarded in 2026
Home Department: Structural Biology
Faculty Advisor: Soichi Wakatsuki (Photon Science and Structural Biology)

Title: Decoding Enzyme Channeling Mechanisms Through Integrated Time-Resolved Structural Biology, Chemical Biology and Molecular Dynamics Simulations

Abstract:
Enzymes are biological catalysts that speed up chemical reactions essential for life. Some enzymes have evolved sophisticated tunnels that transport unstable intermediate molecules directly from one active site to another, a process called substrate channeling. Understanding how these tunnels work could revolutionize drug design and enable the creation of new biosynthetic pathways for medicines and materials. Tryptophan synthase (TS) is a model enzyme that channels indole, a toxic, unstable molecule, through a 25-Å tunnel to produce tryptophan, an essential amino acid. While we know what TS looks like in static snapshots, we do not understand the real-time molecular dynamics: how substrates trigger the reaction, how indole travels through the tunnel, and how distant parts of the enzyme communicate to coordinate chemistry happening 25 Å apart. 

This project integrates three cutting-edge approaches to capture TS "in action": (1) Chemical biology: engineering light-sensitive TS variants using unnatural amino acids that block activity until triggered by laser light, enabling precise reaction control; (2) Time-resolved X-ray crystallography and cryo-electron microscopy to capture molecular movies at micro- to millisecond timescales as substrates flow through; (3) AI-driven modeling connecting structural snapshots into complete mechanistic models. This interdisciplinary approach will reveal fundamental principles of how enzymes control chemical reactions through tunnels and long-range communication, with applications ranging from antibiotic development to designing artificial enzymes for sustainable chemistry.