title: Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
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.
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, United Kingdom. Electronic address: t.collier.12@ucl.ac.uk.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Collier
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nash
authors.affiliation: Institute of Orthopaedics and Musculoskeletal Science, UCL, RNOH Stanmore Campus, London, United Kingdom.
authors.forename: Helen L
authors.initials: HL
authors.lastname: Birch
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, United Kingdom.
authors.forename: Nora H
authors.initials: NH
authors.lastname: de Leeuw
mesh_terms: D000818:Animals; D001665:Binding Sites; D024042:Collagen Type I / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D005109:Extracellular Matrix / Q000737:chemistry*; D017127:Glycation End Products, Advanced / Q000737:chemistry*; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D051381:Rats; D013816:Thermodynamics
chemical_list: D024042:Collagen Type I; D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; C543060:glucosepane; C576840:MMP1 protein, rat; D020781:Matrix Metalloproteinase 1
keywords: Advanced glycation end products; Collagen; Glucosepane; Glycation; Molecular dynamics; Protein cross-linking