- Open Access
Nonequilibrium Remodeling of Collagen IV Networks in Silico
PRX Life 3, 033019 – Published 5 September, 2025
DOI: https://doi.org/10.1103/gdd5-rnh7
Abstract
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. Collagen IV molecules assemble into networks, providing stiffness and elasticity to tissues and informing cell and organ shape, especially during development. In this work, we develop two coarse-grained models for collagen IV molecules that retain biochemical bond specificity and coarse grain at different length scales. Through molecular-dynamics simulations, we test the assembly and mechanics of the resulting networks and measure their response to strain in terms of stress, microscopic alignment, and bond dynamics. Within the basement membrane, collagen IV networks rearrange by molecule turnover, which affects tissue organization and can be linked with enzyme activity. Here we explore network rearrangements via bond remodeling, the process of breaking and remaking of bonds between network molecules. We then investigate the effects of active (enzymatic) bond remodeling. We find that this nonequilibrium remodeling allows a network to keep its integrity under strain, while relaxing fully over a variety of timescales, a dynamic response that is unavailable to networks undergoing equilibrium remodeling.
Physics Subject Headings (PhySH)
Article Text
Supplemental Material
References (99)
- R. Jayadev and D. R. Sherwood, Basement membranes, Curr. Biol. 27, R207 (2017).
- A. L. Fidler, C. E. Darris, S. V. Chetyrkin, V. K. Pedchenko, S. P. Boudko, K. L. Brown, W. Gray Jerome, J. K. Hudson, A. Rokas, and B. G. Hudson, Collagen IV and basement membrane at the evolutionary dawn of metazoan tissues, eLife 6, e24176 (2017).
- N. Khalilgharibi and Y. Mao, To form and function: on the role of basement membrane mechanics in tissue development, homeostasis and disease, Open Biol. 11, 200360 (2021).
- M. A. Morrissey and D. R. Sherwood, An active role for basement membrane assembly and modification in tissue sculpting, J. Cell Sci. 128, 1661 (2015).
- D.-Y. Chen, J. Crest, S. J. Streichan, and D. Bilder, Extracellular matrix stiffness cues junctional remodeling for 3D tissue elongation, Nat. Commun. 10, 3339 (2019).
- J. Candiello, G. J. Cole, and W. Halfter, Age-dependent changes in the structure, composition and biophysical properties of a human basement membrane, Matrix Biol. 29, 402 (2010).
- O. Uspenskaia, M. Liebetrau, J. Herms, A. Danek, and G. F. Hamann, Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels, BMC Neurosci. 5, 37 (2004).
- O. Chaudhuri, J. Cooper-White, P. A. Janmey, D. J. Mooney, and V. B. Shenoy, Effects of extracellular matrix viscoelasticity on cellular behaviour, Nature (London) 584, 535 (2020).
- J. J. Grantham, V. S. Donoso, A. P. Evan, F. A. Carone, and K. D. Gardner, Viscoelastic properties of tubule basement membranes in experimental renal cystic disease, Kidney Int. 32, 187 (1987).
- A. Elosegui-Artola, A. Gupta, A. J. Najibi, B. R. Seo, R. Garry, C. M. Tringides, I. De Lázaro, M. Darnell, W. Gu, Q. Zhou, D. A. Weitz, L. Mahadevan, and D. J. Mooney, Matrix viscoelasticity controls spatiotemporal tissue organization, Nat. Mater. 22, 117 (2023).
- S. Nam, J. Lee, D. Brownfield, and O. Chaudhuri, Viscoplasticity enables mechanical remodeling of matrix by cells, Biophys. J. 111, 2296 (2016).
- L. E. Malvern, Introduction to the Mechanics of a Continuous Medium (Prentice-Hall, Englewood Cliffs, 1969).
- M. Doi and S. F. Edwards, The Theory of Polymer Dynamics (Oxford University Press, Oxford, 1986).
- P.-G. de Gennes, Scaling Concepts in Polymer Physics (Cornell University Press, Ithaca, 1979).
- M. Rubinstein and R. H. Colby, Polymer Physics (Oxford University Press, Oxford, 2003).
- A. E. Likhtman, S. K. Sukumaran, and J. Ramirez, Linear viscoelasticity from molecular dynamics simulation of entangled polymers, Macromolecules 40, 6748 (2007).
- J.-X. Hou, C. Svaneborg, R. Everaers, and G. S. Grest, Stress relaxation in entangled polymer melts, Phys. Rev. Lett. 105, 068301 (2010).
- L. Leibler, M. Rubinstein, and R. H. Colby, Dynamics of reversible networks, Macromolecules 24, 4701 (1991).
- E. B. Stukalin, L.-H. Cai, N. A. Kumar, L. Leibler, and M. Rubinstein, Self-healing of unentangled polymer networks with reversible bonds, Macromolecules 46, 7525 (2013).
- S. Wang and M. W. Urban, Self-healing polymers, Nat. Rev. Mater. 5, 562 (2020).
- R. J. Wagner, E. Hobbs, and F. J. Vernerey, A network model of transient polymers: exploring the micromechanics of nonlinear viscoelasticity, Soft Matter 17, 8742 (2021).
- R. J. Wagner and M. N. Silberstein, A foundational framework for the mesoscale modeling of dynamic elastomers and gels, J. Mech. Phys. Solids 194, 105914 (2025).
- P. Cordier, F. Tournilhac, C. Soulié-Ziakovic, and L. Leibler, Self-healing and thermoreversible rubber from supramolecular assembly, Nature (London) 451, 977 (2008).
- C.-H. Li and J.-L. Zuo, Self-healing polymers based on coordination bonds, Adv. Mater. 32, 1903762 (2020).
- D. Montarnal, M. Capelot, F. Tournilhac, and L. Leibler, Silica-like malleable materials from permanent organic networks, Science 334, 965 (2011).
- W. Denissen, J. M. Winne, and F. E. Du Prez, Vitrimers: permanent organic networks with glass-like fluidity, Chem. Sci. 7, 30 (2016).
- F. Meng, M. O. Saed, and E. M. Terentjev, Rheology of vitrimers, Nat. Commun. 13, 5753 (2022).
- H. Zhao, X. Wei, Y. Fang, K. Gao, T. Yue, L. Zhang, V. Ganesan, F. Meng, and J. Liu, Molecular dynamics simulation of the structural, mechanical, and reprocessing properties of Vitrimers based on a dynamic covalent polymer network, Macromolecules 55, 1091 (2022).
- Y.-C. Lin, G. H. Koenderink, F. C. MacKintosh, and D. A. Weitz, Viscoelastic properties of microtubule networks, Macromolecules 40, 7714 (2007).
- S. Forth and T. M. Kapoor, The mechanics of microtubule networks in cell division, J. Cell Biol. 216, 1525 (2017).
- S. Banerjee, M. L. Gardel, and U. S. Schwarz, The actin cytoskeleton as an active adaptive material, Annu. Rev. Condens. Matter Phys. 11, 421 (2020).
- F. Burla, Y. Mulla, B. E. Vos, A. Aufderhorst-Roberts, and G. H. Koenderink, From mechanical resilience to active material properties in biopolymer networks, Nat. Rev. Phys. 1, 249 (2019).
- R. J. Wagner, S. C. Lamont, Z. T. White, and F. J. Vernerey, Catch bond kinetics are instrumental to cohesion of fire ant rafts under load, Proc. Natl. Acad. Sci. USA 121, e2314772121 (2024).
- R. Price and R. Spiro, Studies on the metabolism of the renal glomerular basement membrane, J. Biol. Chem. 252, 8597 (1977).
- Y. Matsubayashi, B. J. Sánchez-Sánchez, S. Marcotti, E. Serna-Morales, A. Dragu, M.-d.-C. Díaz-de-la Loza, G. Vizcay-Barrena, R. A. Fleck, and B. M. Stramer, Rapid homeostatic turnover of embryonic ECM during tissue morphogenesis, Dev. Cell 54, 33 (2020).
- S. N. Kehlet, N. Willumsen, G. Armbrecht, R. Dietzel, S. Brix, K. Henriksen, and M. A. Karsdal, Age-related collagen turnover of the interstitial matrix and basement membrane: Implications of age- and sex-dependent remodeling of the extracellular matrix, PLoS One 13, e0194458 (2018).
- R. Kalluri, C. F. Shield, P. Todd, B. G. Hudson, and E. G. Neilson, Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis, J. Clin. Invest. 99, 2470 (1997).
- J. M. Sand, L. Larsen, C. Hogaboam, F. Martinez, M. Han, M. R. Larsen, A. Nawrocki, Q. Zheng, M. A. Karsdal, and D. J. Leeming, MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis – validation of two novel biomarker assays, PLoS One 8, e84934 (2013).
- D. G. K. Rasmussen, L. Boesby, S. H. Nielsen, M. Tepel, S. Birot, M. A. Karsdal, A.-L. Kamper, and F. Genovese, Collagen turnover profiles in chronic kidney disease, Sci. Rep. 9, 16062 (2019).
- A. R. Bourgonje, M. S. Alexdottir, A. T. Otten, R. Loveikyte, A.-C. Bay-Jensen, M. Pehrsson, H. M. van Dullemen, M. C. Visschedijk, E. A. M. Festen, R. K. Weersma, M. A. Karsdal, K. N. Faber, J. H. Mortensen, and G. Dijkstra, Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohn's disease, Aliment. Pharmacol. Ther. 56, 675 (2022).
- K. Y. Guerra Santillán, C. Dahmann, and E. Fischer-Friedrich, Elastic contractile stress in the basement membrane generates basal tension in Epithelia, PRX Life 2, 013004 (2024).
- I. T. Rebustini, C. Myers, K. S. Lassiter, A. Surmak, L. Szabova, K. Holmbeck, V. Pedchenko, B. G. Hudson, and M. P. Hoffman, MT2-MMP-dependent release of collagen IV NC1 domains regulates submandibular gland branching morphogenesis, Dev. Cell 17, 482 (2009).
- M. Arden, M. Spearman, and I. Adamson, Degradation of type IV collagen during the development of fetal rat lung, Am. J. Respir. Cell Mol. Biol. 9, 99 (1993).
- A. C. Curino, L. H. Engelholm, S. S. Yamada, K. Holmbeck, L. R. Lund, A. A. Molinolo, N. Behrendt, B. S. Nielsen, and T. H. Bugge, Intracellular collagen degradation mediated by uPARAP/Endo180 is a major pathway of extracellular matrix turnover during malignancy, J. Cell Biol. 169, 977 (2005).
- R. A. Wyatt and B. D. Crawford, Post-translational activation of Mmp2 correlates with patterns of active collagen degradation during the development of the zebrafish tail, Dev. Biol. 477, 155 (2021).
- V. J. Huber, H. Igarashi, S. Ueki, M. Terumitsu-Tsujita, C. Nito, K. Ohno, Y. Suzuki, K. Itoh, I. L. Kwee, and T. Nakada, Visualizing the distribution of matrix metalloproteinases in Ischemic brain using In Vivo 19F-magnetic resonance spectroscopic imaging, Contrast Media Mol. Imag. 2019, 1 (2019).
- A. O'Hara, F.-L. Lim, D. J. Mazzatti, and P. Trayhurn, Microarray analysis identifies matrix metalloproteinases (MMPs) as key genes whose expression is up-regulated in human adipocytes by macrophage-conditioned medium, Pflug. Arch. Eur. J. Physiol. 458, 1103 (2009).
- B. N. Narasimhan and S. I. Fraley, Degradability tunes ECM stress relaxation and cellular mechanics, bioRxiv (2024), doi:10.1101/2024.07.28.605514.
- S. K. Ranamukhaarachchi, A. Walker, M.-H. Tang, W. D. Leineweber, S. Lam, W.-J. Rappel, and S. I. Fraley, Global versus local matrix remodeling drives rotational versus invasive collective migration of epithelial cells, Dev. Cell 60, 871 (2024).
- J. Khoshnoodi, V. Pedchenko, and B. G. Hudson, Mammalian collagen IV, Microsc. Res. Tech. 71, 357 (2008).
- A. Al-Shaer and N. R. Forde, Decoding collagen’s thermally induced unfolding and refolding pathways, Proc. Natl. Acad. Sci. USA 122, e2420308122 (2025).
- A. M. Abreu-Velez and M. S. Howard, Collagen IV in normal skin and in pathological processes, N. Am. J. Med. Sci. 4, 1 (2012).
- M. E. Than, S. Henrich, R. Huber, A. Ries, K. Mann, K. Kühn, R. Timpl, G. P. Bourenkov, H. D. Bartunik, and W. Bode, The 1.9-Å crystal structure of the noncollagenous (NC1) domain of human placenta collagen IV shows stabilization via a novel type of covalent Met-Lys cross-link, Proc. Natl. Acad. Sci. USA 99, 6607 (2002).
- M. Sundaramoorthy, M. Meiyappan, P. Todd, and B. G. Hudson, Crystal structure of NC1 domains structural basis for type IV collagen assembly in basement membranes, J. Biol. Chem. 277, 31142 (2002).
- K. Kühn, H. Wiedemann, R. Timpl, J. Risteli, H. Dieringer, T. Voss, and R. W. Glanville, Macromolecular structure of basement membrane collagens, FEBS Lett. 125, 123 (1981).
- R. Timpl, H. Wiedemann, V. Delden, H. Furthmayr, and K. Kuhn, A network model for the organization of type IV collagen molecules in basement membranes, Eur. J. Biochem. 120, 203 (1981).
- R. Kalluri and D. Cosgrove, Assembly of type IV collagen insights from (IV) collagen-deficient mice, J. Biol. Chem. 275, 12719 (2000).
- P. D. Yurchenco and H. Furthmayr, Type IV collagen “7S” tetramer formation: Aspects of kinetics and thermodynamics, Ann. N.Y. Acad. Sci. 460, 530 (1985).
- A. J. Licup, S. Münster, A. Sharma, M. Sheinman, L. M. Jawerth, B. Fabry, D. A. Weitz, and F. C. MacKintosh, Stress controls the mechanics of collagen networks, Proc. Natl. Acad. Sci. USA 112, 9573 (2015).
- K. A. Jansen, A. J. Licup, A. Sharma, R. Rens, F. C. MacKintosh, and G. H. Koenderink, The role of network architecture in collagen mechanics, Biophys. J. 114, 2665 (2018).
- C. P. Broedersz and F. C. MacKintosh, Modeling semiflexible polymer networks, Rev. Mod. Phys. 86, 995 (2014).
- A. E. Hafner, N. G. Gyori, C. A. Bench, L. K. Davis, and A. Šarić, Modeling fibrillogenesis of collagen-mimetic molecules, Biophys. J. 119, 1791 (2020).
- H. J. Burd, A structural constitutive model for the human lens capsule, Biomech. Model. Mechanobiol. 8, 217 (2009).
- M. H. J. Bailey and M. Wilson, Simulation of defects, flexibility and rupture in biopolymer networks, RSC Adv. 12, 2171 (2022).
- A. E. Hafner, J. Krausser, and A. Šarić, Minimal coarse-grained models for molecular self-organisation in biology, Curr. Opin. Struct. Biol. 58, 43 (2019).
- M. E. Tuckerman, Statistical Mechanics: Theory and Molecular Simulation (Oxford University Press, Oxford, 2023).
- F. S. Gnesotto, F. Mura, J. Gladrow, and C. P. Broedersz, Broken detailed balance and non-equilibrium dynamics in living systems: A review, Rep. Prog. Phys. 81, 066601 (2018).
- D. Mizuno, C. Tardin, C. F. Schmidt, and F. C. MacKintosh, Nonequilibrium mechanics of active cytoskeletal networks, Science 315, 370 (2007).
- A. J. Levine and F. C. MacKintosh, The mechanics and fluctuation spectrum of active gels, J. Phys. Chem. B 113, 3820 (2009).
- Y. Shi, C. L. Porter, J. C. Crocker, and D. H. Reich, Dissecting fat-tailed fluctuations in the cytoskeleton with active micropost arrays, Proc. Natl. Acad. Sci. USA 116, 13839 (2019).
- D. Grober, I. Palaia, M. C. Uçar, E. Hannezo, A. Šarić, and J. Palacci, Unconventional colloidal aggregation in chiral bacterial baths, Nat. Phys. 19, 1680 (2023).
- B. Siebold, R.-q. Qian, R. W. Glanville, H. Hofmann, R. Deutzmann, and K. Kähn, Construction of a model for the aggregation and cross-linking region (7S domain) of type IV collagen based upon an evaluation of the primary structure of the and chains in this region, Eur. J. Biochem. 168, 569 (1987).
- See Supplemental Material at http://link.aps.org/supplemental/10.1103/gdd5-rnh7 for further model details, additional figures and captions for videos 1–4.
- D. Frenkel and B. Smit, Understanding Molecular Simulation: From Algorithms to Applications (Elsevier, Amsterdam, 2023).
- T. Schneider and E. Stoll, Molecular-dynamics study of a three-dimensional one-component model for distortive phase transitions, Phys. Rev. B 17, 1302 (1978).
- A. P. Thompson, H. M. Aktulga, R. Berger, D. S. Bolintineanu, W. M. Brown, P. S. Crozier, P. J. in 't Veld, A. Kohlmeyer, S. G. Moore, T. D. Nguyen, R. Shan, M. J. Stevens, J. Tranchida, C. Trott, and S. J. Plimpton, LAMMPS - a flexible simulation tool for particle-based materials modeling at the atomic, meso, and continuum scales, Comput. Phys. Commun. 271, 108171 (2022).
- A. Stukowski, Visualization and analysis of atomistic simulation data with OVITO—the open visualization tool, Model. Simul. Mater. Sci. Eng. 18, 015012 (2010).
- J. R. Gissinger, B. D. Jensen, and K. E. Wise, REACTER: A Heuristic method for reactive molecular dynamics, Macromolecules 53, 9953 (2020).
- K. Barnard, S. A. Burgess, D. A. Carter, and D. M. Woolley, Three-dimensional structure of type IV collagen in the mammalian lens capsule, J. Struct. Biol. 108, 6 (1992).
- M. Duda, N. J. Kirkland, N. Khalilgharibi, M. Tozluoglu, A. C. Yuen, N. Carpi, A. Bove, M. Piel, G. Charras, B. Baum, and Y. Mao, Polarization of Myosin II refines tissue material properties to buffer mechanical stress, Dev. Cell 48, 245 (2019).
- C.-T. Lee and M. Merkel, Stiffening of under-constrained spring networks under isotropic strain, Soft Matter 18, 5410 (2022).
- S. Dar, R. Tesoro Moreno, I. van Palaia, A. B. Gopalan, Z. G. Sun, L. Strauss, R. Springer, J. M. Belmonte, S. K. Foster, M. Murrell, C. S. Ejsing, A. Šarić, M. Leptin, and A. Diz-Muñoz, Caging of membrane-to-cortex attachment proteins can trigger cellular symmetry breaking, bioRxiv (2024), doi:10.1101/2024.10.14.618153.
- C. A. V. Cruz, H. A. Shaban, A. Kress, N. Bertaux, S. Monneret, M. Mavrakis, J. Savatier, and S. Brasselet, Quantitative nanoscale imaging of orientational order in biological filaments by polarized superresolution microscopy, Proc. Natl. Acad. Sci. USA 113, E820 (2016).
- A. S. Piotrowski-Daspit, B. A. Nerger, A. E. Wolf, S. Sundaresan, and C. M. Nelson, Dynamics of tissue-induced alignment of fibrous extracellular matrix, Biophys. J. 113, 702 (2017).
- C. Monteagudo, M. J. Merino, J. San-Juan, L. A. Liotta, and W. G. Stetler-Stevenson, Immunohistochemical distribution of type IV collagenase in normal, benign, and malignant breast tissue, Am. J. Pathol. 136, 585 (1990).
- B. Meadowcroft, I. Palaia, A.-K. Pfitzner, A. Roux, B. Baum, and A. Šarić, Mechanochemical rules for shape-shifting filaments that remodel membranes, Phys. Rev. Lett. 129, 268101 (2022).
- K. Hayakawa, H. Tatsumi, and M. Sokabe, Actin filaments function as a tension sensor by tension-dependent binding of cofilin to the filament, J. Cell Biol. 195, 721 (2011).
- S.-W. Chang, B. P. Flynn, J. W. Ruberti, and M. J. Buehler, Molecular mechanism of force induced stabilization of collagen against enzymatic breakdown, Biomaterials 33, 3852 (2012).
- A. S. Adhikari, J. Chai, and A. R. Dunn, Mechanical load induces a 100-fold increase in the rate of collagen proteolysis by MMP-1, J. Am. Chem. Soc. 133, 1686 (2011).
- B. P. Flynn, A. P. Bhole, N. Saeidi, M. Liles, C. A. DiMarzio, and J. W. Ruberti, Mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (MMP-8), PLoS One 5, e12337 (2010).
- K. L. Brown, C. F. Cummings, R. M. Vanacore, and B. G. Hudson, Building collagen IV smart scaffolds on the outside of cells, Protein Sci. 26, 2151 (2017).
- C. Battle, C. P. Broedersz, N. Fakhri, V. F. Geyer, J. Howard, C. F. Schmidt, and F. C. MacKintosh, Broken detailed balance at mesoscopic scales in active biological systems, Science 352, 604 (2016).
- G. Paci and Y. Mao, Forced into shape: Mechanical forces in Drosophila development and homeostasis, Semin. Cell Dev. Biol. 120, 160 (2021).
- G. J. Fisher, S. C. Datta, H. S. Talwar, Z.-Q. Wang, J. Varani, S. Kang, and J. J. Voorhees, Molecular basis of sun-induced premature skin ageing and retinoid antagonism, Nature (London) 379, 335 (1996).
- M. A. Karsdal, F. Genovese, E. A. Madsen, T. Manon-Jensen, and D. Schuppan, Collagen and tissue turnover as a function of age: Implications for fibrosis, J. Hepatol. 64, 103 (2016).
- M. Wolosowicz, S. Prokopiuk, and T. W. Kaminski, The complex role of matrix metalloproteinase-2 (MMP-2) in health and disease, Int. J. Mol. Sci. 25, 13691 (2024).
- X. Lu, L. Ding, H. Song, W. Yu, C. Dong, and J. Ren, In situ quantitative measurements on MMP-9 activity in single living cells by single molecule fluorescence correlation spectroscopy, Analyst 148, 752 (2023).
- A. L. Fidler, S. P. Boudko, A. Rokas, and B. G. Hudson, The triple helix of collagens – an ancient protein structure that enabled animal multicellularity and tissue evolution, J. Cell Sci. 131, jcs203950 (2018).
- L. M. Matrisian, The matrix-degrading metalloproteinases, BioEssays 14, 455 (1992).