STRUCTURAL ASPECTS OF OSTEOGENESIS IMPERFECTA

I型胶原是一种纤维蛋白，通常用于 人体结构和功能的完整性。基因突变 这种三螺旋蛋白质的α-1和α-2链诱导 疾病成骨不全(OI)。OI在人中的表达方式是 从一种致命性疾病过程的表型数 只有通过基因分析才能检测到的子宫。我们是 利用分子动力学和自由能技术 微扰以预测表型严重性，由 I型胶原的单点突变。特别是，我们正在 重点调查了以下三个问题：1) 琥珀分子力力场研究的验证 纤维蛋白；2)蛋白质和水蛋白的测定 I型单点突变引起的结构变化 胶原蛋白；3)天然胶原蛋白稳定性变化的测定 胶原蛋白碎片和胶原蛋白碎片中的单点 已经发生了突变。我们已经完成了对琥珀的验证 分子动力学和自由的分子力学力场 胶原蛋白样肽的能量微扰。我们已经决定 该溶剂为胶原蛋白提供了一个稳定的整体网络 分子，但不为三元组提供固有的稳定性 螺旋。我们已经开始与罗恩·瑞恩斯教授在 威斯康星大学确定什么分子 相互作用/影响(例如，氢键、诱导效应) 有助于三螺旋结构的稳定。

Type I collagen is a fibrous protein which is commonly used in the human body for structural and functional integrity. Mutations in the alpha-1 and alpha-2 chains of this triple-helical protein induce the disease Osteogenesis Imperfecta (OI). OI is expressed in people by a number of phenotypes ranging from a disease process that is lethal in utero to one that is only detected through gene analysis. We are using the techniques of molecular dynamics and free energy perturbation to predict the phenotypic severity that result from single point mutations of type I collagen. In particular, we are focusing on the following three issues in our investigation: 1) validation of the AMBER molecular mechanics force field for studying fibrous proteins; 2) determination of protein and water-protein structural changes induced by single point mutations of type I collagen; 3) determination of changes in stability between native collagen fragments and collagen fragments in which a single point mutation has occurred. We have completed the validation of the AMBER molecular mechanics force field for both molecular dynamics and free energy perturbations of collagen-like peptides. We have determined that solvent provides an overall network of stability to the collagen molecule, but does not provide the inherent stability to the triple helix. We have begun a collaboration with Professor Ron Raines at the University of Wisconsin to determine what molecular interactions/effects (e.g., hydrogen bonding, induction effects) contribute to the stability of the triple helix.