Developing a Reactive Molecular Simulation Method for Protein Mechanochemistry

Collagen has recently been found to form radicals when subjected to mechanical stress, followed by detoxification of DOPA radicals via hydrogen peroxide. However, it remains unclear how mechanoradicals reach DOPA. Within the complex environment of the collagen fibril, numerous different reactions are possible, including hydrogen atom transfer (HAT). In this work a combined molecular dynamics (MD) and kinetic Monte Carlo (KMC) method is implemented within an adaptive KMC framework. The developed software, KIMMDY, is capable of simulating long timescale trajectories of reactive condensed phase systems. More than 600 HAT reactions are simulated in a collagen fibril model with up to 20 consecutive reactions. To make MD simulations of amino acid radicals possible, a highly accurate classical force field is trained on QM energies and forces using the Grappa method. Furthermore, a graph neural network is adapted to predict HAT rates for ensembles generated from MD simulations in a novel approach to transition path sampling. These three methodological advances facilitate the application of reactive simulations in the collagen fibril to observe HAT pathways from the homolysis site to the post-translational oxidation product of phenylalanine and tyrosine, DOPA. The DOPA radical can be observed in simulations and kinetic properties confirm the radical scavenger role. Another radical scavenger, pyridinoline (PYD) is proposed and its mechanochemical properties characterised. KIMMDY provides a new perspective on radical reactions in collagen and is designed to be applied to novel molecules and reactions