Descrizione del progetto
Il ruolo dei meccanoradicali nella meccanosensibilità e nell’invecchiamento del collagene
È noto da tempo che i polimeri sintetici sottoposti a stress meccanico generano meccanoradicali mediante rottura dei legami chimici. La natura e la rilevanza biologica dei meccanoradicali nelle proteine rimangono sconosciute. Eppure il collagene è la principale proteina strutturale di numerosi tessuti connettivi organici, il cui invecchiamento è un problema fondamentale in campo sanitario. Il progetto RADICOL, finanziato dall’UE, si propone di indagare il ruolo dei meccanoradicali nell’invecchiamento dei biomateriali con un approccio computazionale e sperimentale. I calcoli di chimica quantistica e le simulazioni di dinamica molecolare permetteranno di identificare i legami e le successive reazioni radicali nel collagene atomistico. Queste previsioni computazionali saranno poi testate da esperimenti biochimici e biofisici. Il progetto getterà nuova luce sulla meccanosensibilità biologica e sull’invecchiamento.
Obiettivo
Our tissues, in particular collagen as the most abundant protein in our body, are constantly exposed to mechanical loads, reaching multiples of the body weight. In artificial polymers, mechanical loads are known for a century to cause radical formation and chemical degradation processes. Mechanoradicals from bond ruptures, being highly reactive and oxidising, deteriorate the material, leading to stiffening and ageing. Ageing of organic tissue is a fundamental problem in health and disease, but a role of mechanoradicals has been a blind spot. Our simple but novel idea is to test the role of mechanoradicals for ageing of biomaterials. As a starting point, we have recently uncovered mechanoradicals in tensed tendon collagen. They readily react with water to form reactive oxygen species (ROS), key signalling molecules in a multitude of physiological processes including ageing.
I hypothesise that mechanoradicals generate a feedback loop resulting in accelerated collagen ageing. Using a scale-bridging combined computational and experimental approach, I will 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. We will perform quantum chemical calculations and Molecular Dynamics (MD) simulations, including a new reactive Monte Carlo/MD scheme, 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 will be 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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
69117 Heidelberg
Germania