MUTATIONAL EFFECTS ON COLLAGEN'S STRUCTURE & STABILITY

描述：（逐字）生物工程集成化学，物理和 应用于生物学和医学的数学科学。的进步 疾病的结构基础和新型生物材料的设计将是 使用上述计算方法和原理获得 以理工科为重包含序列信息分析（生物信息学） 允许在分子水平上对大型生物聚合物进行更直接的研究， 纤维蛋白质如胶原蛋白。 该提案的长期目标是确定结构、物理 和能量性质的生物聚合物使用计算化学方法 包括热力学积分和分子动力学。增加 了解天然和突变体的潜在分子结构 胶原分子将阐明改变的胶原的异常行为 分子。该建议定义了一种计算方法，用于确定 有助于胶原蛋白稳定性的主要力量。这些信息将 提供了一个基础，构建一个能量结构图的 胶原蛋白的三螺旋结构域。这张地图最终将被用作 用于计算遗传筛选方案来预测 成骨不全（OI），作为了解其他 纤维胶原遗传性疾病，并提供详细的分子 设计新型胶原蛋白样生物材料所需的信息。 这一建议的具体目标是：（1）确定主要力量 有助于通过模拟胶原蛋白三螺旋的稳定性， 对同源三聚体胶原蛋白样肽的结构和能量影响;（2） 确定已知突变的螺旋配准的破坏效应 与Ehlers-Danlos综合征（EDS）相关， 甘氨酸取代对二硫键形成的能量效应 在同源三聚体III型胶原片段中;（3）确定能量和 不同取代基对天然序列的结构影响 和I型胶原片段的四个甘氨酸突变体;（4）确定I型胶原片段的甘氨酸突变体的氨基酸序列。 邻居效应和个人贡献的静电，包括 OI区域表型模型的氢键和构象变化; 以及（5）确定计算的热力学量之间的相关性， 与特定突变相关的实验和临床数据 三螺旋。

DESCRIPTION: (Verbatim) Bioengineering integrates chemical, physical and mathematical sciences applied to biology and medicine. Advancements in the structural basis of disease and the design of novel biomaterials will be obtained using computational methods and principles from the above mentioned sciences. Inclusion of the analysis of sequence information (bioinformatics) allows for more direct studies at a molecular level of large biopolymers and fibril proteins such as collagen. The long-term goal of this proposal is to determine the structural, physical and energetic properties of biopolymers using computational chemistry methods including thermodynamic integration and molecular dynamics. An increased understanding of the underlying molecular structure of native and mutant collagen molecules will elucidate the abnormal behavior of altered collagen molecules. This proposal defines a computational approach for determining the major forces contributing to the stability of collagen. This information will provide a foundation for constructing an energetic-structural map of the triple-helical domain for collagen. This map will ultimately be used as a basis for a computational genetic screening protocol to predict the phenotype of Osteogenesis Imperfecta (OI), serve as the foundation for understanding other fibril collagenous genetic disorders, and provide the detailed molecular information required for the design of novel collagen-like biomaterials. The specific aims of this proposal are: (1) determine the major forces contributing to the stability of the collagen triple-helix by simulating the structural and energetic effects on homotrimer collagen-like peptides; (2) determine the disruption effects of helix registration for known mutations associated with Ehlers-Danlos Syndrome (EDS) by simulating the structural and energetic effects that a glycine substitution has on disulfide bridge formation in the homotrimer type III collagen fragments; (3) determine the energetic and structural effects of different substituents on a naturally occurring sequence and four glycine mutants for a type I collagen fragment; (4) determine the neighborhood effects and individual contributions of electrostatics including hydrogen bonds and conformational changes for the OI regional phenotype model; and (5) determine the correlation among the computed thermodynamic quantities, experimental and clinical data associated with a particular mutation in the triple helix.