Nonequilibrium Remodeling of Collagen IV Networks in Silico

Collagen IV is one of the main components of the basement membrane, a layer of material that lines the majority of tissues in multicellular organisms. It assembles into networks, providing stiffness and elasticity to tissues and informing cell and organ shape, especially during development. We develop two coarse-grained models for collagen IV molecules and through molecular-dynamics simulations, we test the assembly and mechanics of the resulting material. A key biological question is whether the network is breaking and reforming its bonds, and whether this happens passively or actively (consuming energy). We investigate the effects of active bond remodeling and find it allows a network to keep its integrity under strain, while relaxing fully over a variety of timescales, a dynamic response that is unavailable to equilibrium networks. The novelty of the model lies in its ability to operate at a scale (tens of thousands of molecules) that directly connects with tissue-level experiments. This has enabled simulations to be converted into “mimic-microscopy” images and analysed using the same alignment tools as in experiment, uncovering that non-equilibrium remodelling underpins relaxation in ex vivo tissues. In parallel, the model has quantified how molecular turnover governs stress-relaxation timescales, bridging the gap from microscopic remodelling, which can be measure experimentally, to mechanics that can be captured by simple mathematical models of tissues.