Electron Transport through a Tryptophan Quadruplex in a Dimeric Azurin Construct

A tryptophan quadruplex at a protein-protein interface in a dimeric azurin construct mediates 8-11 ns intramolecular as well as interfacial electron hole transfer (HT) triggered by ultrafast photooxidation by a covalently attached organometallic chromophore (Takematsu et al. J . Phys . Chem . B ., 2019, 123, 1578-1591). MM/MD and QM/MM/MD simulations characterized intermediates of through-quadruplex HT (i.e., states with one of the tryptophans oxidized) and assessed the feasibility of individual HT pathways. Simulations demonstrated that the oxidized quadruplex in aqueous solution occurs in four distinct states where the charge is predominantly (≥90%) localized at individual tryptophan indoles. Distributions of indole-indole distances, electronic couplings, as well as electrostatic potentials at indoles indicate kinetic and energetic preferences of interfacial over intramolecular ET. Interfacial indoles are tightly solvated by a chain of quasi-structural water molecules that are shielded from bulk water by protein folds. Solvating water molecules support ET by 0.1-0.2 Å shifts toward positively charged indoles. PDB search revealed that 4-Trp clusters are rather common among naturally occurring oxidoreductases. ; © 2026 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0. ; This work was supported by the Czech Science Foundation grant 21-05180S, the “Energy Conversion and Storage” project CZ.02.01.01/00/22_008/0004617 of the Johannes Amos Commenius program, and the Czech Ministry of Education (MEYS) grant LUAUS25012. The research at the California Institute of Technology was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01GM159231. Additional support was provided by the Arnold and Mabel Beckman Foundation. M.M. and J.H. acknowledge the Specific university research grant No. A1_FCHI_2025_001. Computational resources were provided by the e-INFRA CZ project (ID:90254), MEYS C̆R. We thank Jay R. ...