Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study

Thomas A Collier,Anthony Nash,Helen L Birch,Nora H De Leeuw

doi:10.1016/j.matbio.2015.06.001

Thomas A Collier, Anthony Nash + Show 2 more

Open Access

https://doi.org/10.1016/j.matbio.2015.06.001

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Journal: Matrix Biology	Publication Date: Jun 4, 2015
Citations: 24	License type: cc-by

Affiliation: University College London

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.

Highlights

Collagen plays an important structural role in the extracellular matrix (ECM) of all vertebrates and accounts for over a quarter of the dry mass of the human body [1,2]
A distance-based criterion search is used within a model collagen molecule to identify lysine and arginine residues within 5 Å of one another
We identify whether a site is a likely candidate for glucosepane formation if the total energy of the collagen molecule is lower in the presence of a bound glucosepane cross-link compared to an unbound glucose molecule

Summary

Introduction

Collagen plays an important structural role in the extracellular matrix (ECM) of all vertebrates and accounts for over a quarter of the dry mass of the human body [1,2]. The skeletal and other connective tissues show a gradual decline in their ability to function effectively and the incidence of injury and disease increases [4] These changes occur, in part, due to adventitious chemical modifications to collagen over time, such as the addition of sugars (glycation) and the formation of advanced glycation end products (AGEs) [5]. According to the Hodge–Pertruska model, the collagen molecules line up in a parallel staggered side-by-side arrangement to form hydrated fibrils, shown in Fig. 1 [6]. These collagen fibrils have varying lengths and diameters dependent on the organism and location of the tissue. For example in human Achilles tendon average fibril diameters of 50–90 nm have been measured whereas in the flexors and extensors of the fingers diameters are (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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