Lecture 3: Decoding the atomic structure of bone: molecular insights into brittle bone disease

Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to organisms. Normal type I collagen is a heterotrimer and consists of two alpha-1 chains and one alpha-2 chain. A mouse model of the genetic brittle bone disease, osteogenesis imperfect (oim), is characterized by a replacement of the alpha-2 chain by a alpha-1 chain, resulting in a homotrimer collagen molecule. Experimental studies of oim mice tendon and bone have shown reduced mechanical strength compared to normal mice. How the molecular mutation affects the packing of collagen molecules at the microfibril level and the relationship between the molecular content and the decrease in strength is, however, still not clear. In this study, we use molecular simulations to study the structural and mechanical differences between the heterotrimer and homotrimer collagen microfibrils. The collagen microfibril models are generated based on the in situ structure of full length collagen type I molecule with the actual amino acid sequence of real mouse collagen. Through a detailed structural analyses, our results suggest that the oim microfibril is less dense compared to the normal microfibril as a result of local kink formations which explains the reduction of modulus of the oim microfibril. Our studies provide fundamental insight of the effect of the loss of alpha-2 chain at the molecular level and help understanding the molecular origin of the bone brittle disease at much larger length-scales.