Hybrid Kinetic Monte Carlo/Molecular Dynamics Simulations of Bond Scissions in Proteins

Abstract

Proteins are exposed to various mechanical loads that can lead to covalent bond scissions even before macroscopic failure occurs. Knowledge of these molecular breakages is important to understand mechanical properties of the protein. In regular Molecular Dynamics (MD) simulations, covalent bonds are predefined and reactions cannot occur. Furthermore, such events rarely take place on MD timescales. Existing approaches that tackle this limitation either rely on computationally expensive quantum calculations or complex bond order formalisms in force fields. To circumvent these limitations, we have developed a new reactive Kinetic Monte Carlo / Molecular Dynamics (KIMMDY) scheme. Here, bond rupture rates are calculated in the spirit of a transition state model based on the interatomic distances in the MD simulation and then used as an input for a Kinetic Monte Carlo step. This drastically increases the accessible timescales for reactive MD simulations. Using this new technique, we investigated bond ruptures in a multi-million atom system of tensed collagen, a structural protein found in skin, bones and tendons. Our simulations show a clear concentration of homolytic bond scissions near chemical crosslinks in collagen, consistent with our recent Electron Paramagnetic Resonance (EPR) experiments on collagen type I under stretch. We suggest that these created mechanoradicals are a yet unknown connection converting mechanical into oxidative stress. This application also demonstrates that our hybrid computational approach is easily scalable and exhibits only a minor slowdown compared to classical MD. It is straightforwardly applicable to address related questions for other biomaterials with coupled mechanical and chemical processes.