Introducing non-enzymatic crosslinks into atomistic simulations of collagen fibrils

Abstract

Motivation: Collagen fibrils are the primary load-bearing units of connective tissues. However, generating atomistic, simulation-ready models remains challenging due to collagen's hierarchical organization and the diversity of its crosslinking network across tissues, ages, and metabolic states. Notably, non-enzymatic advanced glycation end-product (AGE) crosslinks, central to aging and diabetic complications, are largely absent from current atomistic fibril modelling workflows. Results: Here, we present an extension of the ColBuilder framework to generate atomistic collagen fibril models that incorporate three representative AGE-derived crosslinks (glucosepane, pentosidine, and MOLD) alongside enzymatic crosslinks. Amber99-compatible parameters are provided and assessed against QM-optimized reference geometries using all-atom molecular dynamics (MD) simulations. As proof-of-concept, we examine the mechanical response of single D-period collagen microfibrils featuring enzymatic-only, AGE-only, and mixed crosslink patterns in Molecular Dynamics simulations under force, and observe that AGE crosslinks differently impact the fibril structure compared to enzymatic crosslinks. The extension to ColBuilder can aid future structure-based research on collagen aging. Availability and implementation: ColBuilder is available as an open-source Python command-line package at https://github.com/graeter-group/colbuilder.