Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
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DOI：
10.1016/j.matbio.2015.06.001
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
de Leeuw NH
中科院分区：
文献类型：
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作者：
Collier TA;Nash A;Birch HL;de Leeuw NH
细胞外基质（ECM）经历渐进的年龄相关的硬化和蛋白水解消化率的损失，由于浓度的增加，先进的糖化终末产物（AGEs）。最丰富的AGE，glucosepane，在胶原蛋白中积累，浓度超过所有其他AGE的100倍。有害的胶原硬化特性被认为在几种与年龄相关的疾病如骨质疏松症和心血管疾病中起重要作用。目前，很少有人知道胶原蛋白分子内共价交联glucosepane形成的潜在位置;也没有关于各自的交联位点如何影响胶原蛋白的物理和生物化学性质的报道。使用完全原子分子动力学模拟（MD），我们已经确定了六个网站，其中形成一个共价的分子内glucosepane交联在一个单一的胶原蛋白分子在纤维环境中是积极有利的。这些有利的网站的识别，使我们能够对齐胶原交联与实验观察到的ECM的变化。例如，发现glucosepane的形成在基质金属蛋白酶-1（MMP 1）结合位点附近是能量上有利的，这可能潜在地破坏胶原蛋白降解。我们进行了完全原子分子动力学模拟纤维胶原蛋白。在六个位置上，葡糖烷交联形成是积极有利的。鉴定的位置在关键胶原蛋白生物分子位点内。部位的定位可能对组织功能和完整性有显著影响。
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. We conduct fully atomistic molecular dynamics simulation of fibrillar collagen. Glucosepane cross-link formation is energetically favourable at six positions. Positions identified are within key collagen biomolecule sites. Positioning of sites may have a significant effect on tissue function and integrity.