Intra-molecular lysine-arginine derived advanced glycation end-product cross-linking in Type I collagen: A molecular dynamics simulation study

Abstract

Covalently cross-linked advanced glycation end products (AGE) are among the major post-translational modifications to proteins as a result of non-enzymatic glycation. The formation of AGEs has been shown to have adverse effects on the properties of the collagenous tissue; they are even linked to a number of age related disorders. Little is known about the sites at which these AGEs form or why certain sites within the collagen are energetically more favourable than others. In this study we have used a proven fully atomistic molecular dynamics approach to identify six sites where the formation of the intra-molecular 3-deoxyglucosone-derived imidazolium cross-link (DOGDIC) is energetically favourable. We have also conducted a comparison of these positions with those of the more abundant glucosepane cross-link, to determine any site preference. We show that when we consider both lysine and arginine AGEs, they exhibit a prevalence to form within the gap region of the collagen fibril.

Keywords: Advanced glycation end products; Collagen; DOGDIC; Glucosepane; Glycation; Molecular dynamics; Protein cross-linking.

Fig. 1

Schematic image of Lysine (R₁)-Arginine (R₂) cross-linking AGEs, A) Glucosepane B) DOGDIC, C) MODIC and D) GODIC.

Fig. 2

Shows a collagen molecule with A. gap regions highlighted in orange, B. the favourable (green) and unfavourable (red) potential glucosepane cross-linking sites C. the favourable (green) and unfavourable (red) potential DOGDIC cross-linking sites.

Fig. 3

Local environment around the favourable DOGDIC cross-link sites a) Position 4, b) Position 11, c) Position 18, d) Position 19, e) Position 20 and f) Position 21. (Residue colours: Ala — blue; Asn — tan; Asp — red; Arg — lime; Gln — orange; Glu — pink; Gly — ice blue; His — violet; Hyp — silver; Ile — grey; Leu — black; Lys — yellow; Met — white; Phe — purple; Pro — ochre; Ser — light blue; Thr — mauve; Tyr — magenta; Val — gold); glucosepane cross-link shown as sticks.