Linking Collagen Genotypes to Molecular Phenotypes

描述（由申请人提供）： 胶原蛋白是人类最丰富的蛋白质，胶原蛋白的突变可能导致死亡或疾病。个别突变影响胶原蛋白结构/功能的方式知之甚少。胶原蛋白是一种纤维状蛋白质，因此许多为研究球状蛋白质而阐明的原理并不能立即应用于研究其结构和功能之间的关系。我们现在有机会使用基因组技术来调查整个人群中关键胶原基因的变异，将发现的多态性与其结构效应联系起来，并了解胶原性疾病的机制。这项工作也将为设计新的治疗方法和设计新型胶原样生物材料提供基础。 该提案的长期目标是确定生物聚合物在自然序列变异背景下的化学、物理和结构特性。我们将利用我们在基因组学和结构生物学方面的联合能力来实现以下具体目标：（1）在不同种族的人群中鉴定单核苷酸多态性（SNP），以确定胶原基因COL 1A 1，COL 1A 2，COL 2A 1和COL 3A 1的背景遗传变异，然后确定SNP在胶原疾病个体中的分布;（2）对胶原蛋白样肽和全长I型和III型胶原蛋白三螺旋进行建模，以确定由胶原蛋白样肽中的单点甘氨酸取代和全长胶原蛋白模型中的遗传变异引起的结构和能量效应; (3)开发分析工具，将在分子动力学模拟中观察到的功能和表型结合起来，以构建OI相关突变的I型胶原的工作模型;以及（4）开发模拟天然和突变型胶原样肽的折叠和解折叠的方法，以确定由具有表型后果的突变诱导的效应。

DESCRIPTION (provided by applicant): Collagen is the most abundant protein in humans, and mutations in collagen can lead to death or disease. The ways in which individual mutations affect collagen structure/function are poorly understood. Collagen is a fibrillar protein, and thus many of the principles elucidated for the study of globular proteins are not immediately applicable in investigating the relationship between its structure and function. We now have an opportunity to use genomic technologies to survey the variation in key collagen genes throughout the human population, link the discovered polymorphisms to their structural effects, and develop an understanding of the mechanism of collagenous disorders. This work will also provide a foundation for engineering new treatments and the designing of novel collagen-like biomaterials. The long-term goal of this proposal is to determine the chemical, physical and structural properties of biopolymers in the context of natural sequence variation. We will take advantage of our joint capabilities in genomics and structural biology to pursue the following specific aims: (1) to identify Single Nucleotide Polymorphisms (SNPs) in an ethnically diverse population to determine the background genetic variation across the collagen genes COL1A1, COL1A2, COL2A1 and COL3A1 and then determine the distribution of SNPs in individuals with collagen disorders; (2) to model collagen-like peptides and full-length Type I and Type III collagen triple helices to determine the structural and energetic effects resulting from single point glycine substitutions in the collagen-like peptides and genetic variation in the full-length collagen models.; (3) to develop analysis tools that incorporate function and phenotypes observed in molecular dynamics simulations to construct a working model of type I collagen for OI-associated mutations; and, (4) to develop methods to simulate the folding and unfolding of native and mutant collagen-like peptides to determine the effects induced by mutations with phenotypic consequences.