The role of type I collagen heterotrimers and homotrimers in mechanical strength and collagen cleavage

Collagen is a crucial structural protein, formed through a hierarchical assembly of molecules, arranged in collagen fibrils, which constitutes the basis for larger-scale fibers. Normal type I collagen is a heterotrimer triple-helical molecule consisting of two alpha-1 chains and one alpha-2 chain. A mouse model of the genetic brittle bone disease, osteogenesis imperfecta, oim, is characterized by a replacement of the alpha-2 chain by an 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. The relationship between the molecular content and the decrease in strength is, however, still unknown. In this thesis, we use a bottom-up molecular simulation approach to examine the role of type I normal collagen and oim collagen from a single collagen molecule to collagen microfibril to mineralized collagen microfibril. At the molecular level, we find that the replacement of the alpha-2 chain results in a collagen molecule with more kinks and a more thermally stable cleavage site. The higher thermal stability of the cleavage site of the homotrimer explains the enzyme resistances of homotrimers. Furthermore, we reveal a molecular mechanism of force induced stabilization of collagen against enzymatic breakdown for the heterotrimer. At the fibril level, we find that the kinks affect the packing of collagen molecules. The homotrimer microfibril has a less dense packing of collagen molecules which leads to a reduced modulus. The alterations on the assembly of collagen molecules further alter the space for mineral deposition at the mineralized collagen fibril level. We find that the mineralized homotrimer collagen fibril has more space for mineral deposition but the mineral size is smaller because the kinks at the molecular level result in a more discontinuous space for mineral deposition. The mineralized oim collagen microfibril has a reduced modulus due to the alterations on the collagen assembly and mineral deposition. Our results provide fundamental insight into the effect of the loss of alpha-2 chain at the molecular level and help understanding the molecular origin of many diseases such as the brittle bone at much larger length-scales.

Department dc:contributor.department

Massachusetts Institute of Technology. Department of Civil and Environmental Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2014

Author dc:creator

• Chang, Shu-Wei, Ph. D. Massachusetts Institute of Technology

Advisor dc:contributor.advisor

• Markus J. Buehler.

• Civil and Environmental Engineering.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/95567

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/95567