Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Department of Chemistry, University of Warwick, Coventry, UK.
Proteins. 2021 May;89(5):521-530. doi: 10.1002/prot.26036. Epub 2020 Dec 23.
The accumulation of advanced glycation end-products is a fundamental process that is central to age-related decline in musculoskeletal tissues and locomotor system function and other collagen-rich tissues. However, although computational studies of advanced glycation end-product cross-links could be immensely valuable, this area remains largely unexplored given the limited availability of structural parameters for the derivation of force fields for Molecular Dynamics simulations. In this article, we present the bonded force constants, atomic partial charges and geometry of the arginine-lysine cross-links DOGDIC, GODIC, and MODIC. We have performed in vacuo Molecular Dynamics simulations to validate their implementation against quantum mechanical frequency calculations. A DOGDIC advanced glycation end-product cross-link was then inserted into a model collagen fibril to explore structural changes of collagen and dynamics in interstitial water. Unlike our previous studies of glucosepane, our findings suggest that intra-collagen DOGDIC cross-links furthers intra-collagen peptide hydrogen-bonding and does not promote the diffusion of water through the collagen triple helices.
糖基化终产物的积累是一个基本过程，它与肌肉骨骼组织和运动系统功能以及其他富含胶原蛋白的组织的衰老有关。然而，尽管计算糖基化终产物交联的研究可能具有巨大的价值，但由于用于分子动力学模拟的力场推导的结构参数有限，这个领域在很大程度上仍未得到探索。在本文中，我们提出了精氨酸-赖氨酸交联 DOGDIC、GODIC 和 MODIC 的键力常数、原子部分电荷和几何形状。我们进行了真空分子动力学模拟，以验证它们在与量子力学频率计算的对比中的实现。然后，将一个 DOGDIC 糖基化终产物交联插入模型胶原原纤维中，以探索胶原的结构变化和间质水中的动力学。与我们之前对葡萄糖醛酮的研究不同，我们的发现表明，胶原内的 DOGDIC 交联进一步促进了胶原内肽的氢键形成，而不会促进水通过胶原三螺旋的扩散。
