Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils
Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils
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DOI：
10.1016/j.bpj.2009.04.059
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发表时间：
2009-08-05
影响因子：
3.4
通讯作者：
Buehler, Markus J.
中科院分区：
文献类型：
--
作者：
Gautieri, Alfonso;Uzel, Sebastien;Buehler, Markus J.
成骨不全(OI)是一种胶原的遗传性疾病，其特征是肌腱机械削弱、骨骼脆弱、骨骼畸形，严重时可导致产前死亡。尽管许多研究试图将特定的突变类型与表型严重程度联系起来，但单点突变在多个长度尺度上影响组织机械行为的分子和中尺度机制仍不清楚。我们通过全原子和中尺度的层级模拟表明，从单分子到胶原纤维，OI突变在多个尺度上严重损害了胶原组织的机械性能。导致最严重的OI表型的突变与最强的效应相关，导致分子间粘附性减弱，分子间间距增加，刚性降低，以及胶原纤维的断裂强度降低。我们发现，这些分子水平的变化导致突变的胶原纤维中应力分布的改变，导致应力集中的形成，从而通过分子间滑移导致材料破坏。我们相信，我们的发现为这种疾病的微观机制提供了洞察力，并导致了对OI组织特征的解释，如机械强度降低和交联剂密度降低。我们的研究解释了单点突变如何在更大的长度范围内控制组织的分解，这是一个与广泛类别的遗传病非常相关的问题。
Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases.