Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study
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Date
2015-06-01
Open Access Location
Authors
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Journal ISSN
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Publisher
Elsevier
Rights
Open Access funded by Biotechnology and Biological Sciences Research Council under a Creative Commons license
Abstract
The extracellular matrix (ECM) undergoes progressive age-related stiffening and loss of proteolytic digestibility due to an increase in concentration of advanced glycation end products (AGEs). The most abundant AGE, glucosepane, accumulates in collagen with concentrations over 100 times greater than all other AGEs. Detrimental collagen stiffening properties are believed to play a significant role in several age-related diseases such as osteoporosis and cardiovascular disease. Currently little is known of the potential location of covalently cross-linked glucosepane formation within collagen molecules; neither are there reports on how the respective cross-link sites affect the physical and biochemical properties of collagen. Using fully atomistic molecular dynamics simulations (MD) we have identified six sites where the formation of a covalent intra-molecular glucosepane cross-link within a single collagen molecule in a fibrillar environment is energetically favourable. Identification of these favourable sites enables us to align collagen cross-linking with experimentally observed changes to the ECM. For example, formation of glucosepane was found to be energetically favourable within close proximity of the Matrix Metalloproteinase-1 (MMP1) binding site, which could potentially disrupt collagen degradation.
Description
Keywords
Collagen, Glycation, Molecular dynamics, Protein cross-linking, Glucosepane, Advanced glycation end products
Citation
Matrix Biology, 2015, 48 pp. 78 - 88