Periodic Reporting for period 1 - RADICOL (Mechanoradicals in Collagen)
Période du rapport: 2021-06-01 au 2022-11-30
Our aim is to test the hypothesis that mechanoradicals generate a feedback loop resulting in accelerated collagen ageing. Using a scale-bridging combined computational and experimental approach, we dissect the full lifecycle of mechanoradicals in collagen, from bond scission and radical migration to ROS formation, to uncover new mechanisms of radical-mediated ageing. Our methods include quantum chemical calculations and Molecular Dynamics (MD) simulations, a new reactive Monte Carlo/MD scheme, in order to identify scissile bonds and subsequent radical reactions in atomistic collagen I fibril models. For validation, a combination of electron-paramagnetic resonance spectroscopy, mass spectrometry and other biophysical experiments is employed to measure degradation pathways, radicals and ROS under varying crosslink densities and types as present in young, aged and diseased tendon tissues.
RADICOL will establish protein mechanoradicals as an as yet uncovered source of oxidative stress, and as a new paradigm of biological mechanosensation and ageing.
All of our simulation work is based on our structural model of collagen, which we made available publicly and which includes a number of chemically different crosslinks as well as different collagen sequences [Obarska-Kosinska et al, 2021].
OVerall, the project will lead to a first quantitative view on how mechanoradicals are formed and processed by collagen, and how collagen has been designed to cope with them, shedding new light on tissue ageing and disease.