Enzymatic and non-enzymatic cross-links in collagen

In an aging society fracture of bone that leads to a loss of mobility and quality of life is one of the biggest challenges. Diabetes mellitus, a metabolic disease, characterized by the disability of the organism to control the sugar levels in the blood, has also detrimental effects on bone. The organic component of bone, the triple helical protein collagen provides the template upon which bone mineralization occurs and is also responsible for certain mechanical attributes of bone. These mechanical attributes are carefully tuned by enzymatically cross-linking different collagen molecules. These cross-links are placed at well-defined locations in the molecule. In contrast to enzymatic cross-links, non-enzymatic cross-links are detrimental to the mechanical performance of bone. These can occur anywhere in the molecule and accumulate with age. As non-enzymatic cross-links are formed via glycation, increased glucose levels in the blood stream, as found in diabetes, accelerate this natural aging process. A large amount of non-enzymatic cross-links leads to a brittle material that is prone to fracture.

In this project, we will investigate the change of collagen properties with aging and disease induced by a change in the cross-linking pattern. We will use computational as well as experimental methods. Spectroscopic methods allow to assess the number and type of cross-links. Scanning acoustic microscopy gives the possibility to measure the local mechanical properties of collagen. In parallel to the measurements, the molecular structure of different types of cross-links will be modeled in the computer. Their mechanical properties will be calculated by deforming these structures in silico. The knowledge of the mechanical behavior of single cross-links can then be used to deform larger structures, like a collagen fibril, consisting of many different cross-links. The number and type of cross-links known from experiment are an important input for the simulations. On the other hand, the simulations allow for the testing of different spatial configurations of cross-links; an information that is not accessible in the experiments. It is this combination of experimental and theoretical methods that make this project unique and that will allow for new findings that cannot be obtained otherwise.