Structural and environmental effects on the mechanism of biological proton-coupled electron transfer using DFTB/MM metadynamics

Proton-coupled electron transfer (PCET) between non-metallic molecules plays an important role in several biological processes involving the oxidation and reduction of aromatic cofactors and amino acids such as tyrosine and tryptophan. Computational chemistry approaches based on quantum-classical multi-scale description can provide atomic insights to understand how a complex biomolecular structure can tune PCET mechanisms. However, the dynamical description of the environment is limited by the cost of the quantum method. In this work, we propose a protocol based on the efficient DFTB3 method and one-dimensional metadynamics at a nanosecond timescale to generate ground-state free energy surfaces of PCET. The proton transfer coordinate is biased in the simulation, while the electron transfer coordinate is evaluated <i>a posteriori</i> through calculations of the difference in molecular charges with an improved DFTB Hamiltonian. This procedure was tested for several biomimetic peptides in QM/MM simulations, involving tyrosine, tryptophan and histidine residues. We found that the adiabatic mechanism of PCET in the studied biomimetic peptides depends not only on the orientation of the donor and acceptor residues but also on environmental factors. Specifically, we demonstrate how interactions between the reaction center and nearby protein components, as well as solvent exposure, influence both the mechanism and kinetics of PCET. Additionally, we identify two distinct concerted PCET mechanisms between tyrosine side chains: fully synchronous and potentially asynchronous. Our results constitute a first validation of this efficient QM/MM protocol for detailed investigation of the structural and dynamical aspects of biological PCET.