Influence of Non-Cross-Linking AGEs on Mechanical Properties and Morphological Features of Tropocollagen Peptides: A...

Collagen, a protein known for its long lifespan, is susceptible to accumulation of advanced glycation end products (AGEs) with age. These AGEs are considered markers that indicate the aging severity and influence the mechanics of tissues, leading to fragile bones and hardened skin. While many cross-linking AGEs have been widely studied for their ability to reduce the elasticity of biological tissues, contributing to skin hardening and fragile bones, through strong covalent bonds, non-cross-linking AGEs, or AGE adducts, are typically investigated as indicators of aging or as signaling factors in pathological conditions. However, recent experimental findings have revealed that the number of AGE adducts in aged bone is comparable to enzymatic cross-links, which are significantly more abundant than cross-linking AGEs. Based on these observations, we consider one of the most abundant AGE adducts - carboxymethyllysine (CML) - and employ molecular dynamics simulations to explore its direct impact on the mechanical and conformational properties of single tropocollagen molecules. Our models demonstrate that tropocollagen peptides, constructed based on sequences experimentally identified with sites of CML modifications in type I collagen derived from human cortical bone, exhibit heterogeneous behaviors under tensile testing. Still, most of these modified peptides display compromised structural stability, reduction in structural strength, and diminished energy dissipation ability when tension is applied. This study highlights the potential impact of non-cross-linking AGEs on collagen behavior at molecular scale and provides insights into the mechanisms underlying these modifications. Gaining a deeper understanding of the role of AGE adducts and their contribution to the aging process may pave the way for future solutions in antiaging research.