One way to study biological structures is to dissect or visualize them. Another is to actually model the molecular structure of the material and run computer simulations to study how it functions. MIT researchers have now used the modeling technique called “materiomics” to study how collagen behaves in patients suffering from osteogenesis imperfecta. Here are the basics of the study findings from the MIT news room:
In what may be the first detailed molecular-based multi-scale analysis of the role of a materials’ failure in human disease, a paper in the Aug. 5 issue of Biophysical Journal describes exactly how the substituted amino acid repels other amino acids rather than forming chemical bonds with them, creating a radically altered structure at the nanoscale that results in severely compromised tissue at the macroscale. This approach to the study of disease, referred to as “materiomics” by the lead researcher on the project, Professor Markus Buehler of MIT’s Department of Civil and Environmental Engineering, could prove valuable in the study of other diseases – particularly collagen- and other protein-based diseases – where a material’s behavior and breakdown play a critical role.
Three years ago, Buehler used atomistic-based multi-scale modeling to describe in detail the hierarchical structure of collagen, the tissue comprising most structural material in mammalian bodies. His model incorporates a bottom-up description of collagen, accounting for the hierarchical assembly of molecules, each of which consists of three helical threads of amino acids. The molecules are arranged in packets called fibrils that collectively make up whole tissue.
In new research, Buehler and Sebastien Uzel, a graduate student at MIT, and Alfonso Gautieri, Alberto Redaelli and Simone Vesentini of Politecnico di Milano modeled type I collagen’s behavior at the atomistic level all the way up to the scale of the fibrils that make up whole tissue.
The different forms of severity in brittle bone disease correlate with a particular genetic mutation; some amino acid substitutions for glycine create more severe forms of osteogenesis imperfecta.
Using atomistic modeling, the researchers demonstrate exactly how the substitution of eight different amino acids in place of glycine changes the electrochemical behavior of the collagen molecules and affects the mechanical properties of the collagen tissue. They learned that the mutations creating the most severe form of the disease also correlate with the greatest magnitude of adverse effects in creating more pronounced rifts in the tissue, which lead to the deterioration and failure of the tissue.
Image: The image at top depicts a healthy collagen fibril. The image below it depicts a fibril with brittle bone disease displaying the small rifts (in orange) that form in collagen tissue at the sites where an incorrect amino acid has been substituted for glycine.
Press release: Tiny rifts create fragility of brittle bone disease
Abstract in Biophysical Journal: Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils