MOLECULAR CONFORMATION, COMPARISON AND INTERACTION

大量的结构信息正从X射线 蛋白质和蛋白质的晶体学和2D NMR光谱学 配体。 因为生物活性取决于分子形状， 比较蛋白质的形状和构象是很重要的， 药物客观准确。 为了使方法客观， 它必须在不同的人手中产生相同的结果。 这不是 在一种颜色上交互叠加两种结构的情况 计算机图形屏幕。 因此，有必要制定 分子比较的自动计算机算法。 一 成功算法必须（i）避免指定不同的 结构相似，（ii）反之亦然。 该提案提出 一种蛋白质构象比较方法， 第一个目标是考虑拓扑结构，而不仅仅是 蛋白质构象的几何学。 小分子比较 算法通过使用最大化来实现第二个目标 重叠的化学体积，以确定结构与类似 形状和类似放置的功能组，即使当 基本的化学结构完全不同。 第三个项目 将开发一种自动算法， 口袋和对接小分子，如药物和 荷尔蒙，进入他们。 这三个项目都将是跨学科的 并将基于应用微分几何，计算机 科学和计算机图形学来研究构象， 蛋白质和药物的化学和相互作用。 蛋白质 构象比较方法将计算分子中的路径 连接两个给定构象的构象空间 蛋白质或两种密切相关的蛋白质。 这将有助于在 了解蛋白质的构象转变和结构 由于位点特异性诱变实验或自然 进化和变异，包括点突变疾病。 的 小分子比较法有助于合理用药 设计

A wealth of structural information is being accumulated from X-ray crystallography and 2D NMR spectroscopy of proteins and protein ligands. Because biological activity depends on molecular shape, it is important to compare shapes and conformations of proteins and drugs objectively and accurately. For a method to be objective, it must produce the same results in different hands. This is not the case for interactive superposition of two structures on a color computer graphics screen. It is therefore necessary to develop automatic computer algorithms for molecular comparison. A successful algorithm must (i) avoid designating dissimilar structures as similar, and (ii) vice versa. This proposal presents a protein conformation comparison method that accomplishes the first objective by taking into account the topology, not just the geometry, of protein conformations. A small molecule comparison algorithm accomplishes the second objective by using maximization of overlap of chemical volume to identify structures with similar shapes and similarly placed functional groups, even when the underlying chemical structure is quite different. A third project will develop an automatic algorithm for identifying protein binding pockets and for docking small molecules, such as drugs and hormones, into them. All three projects will be inter-disciplinary and will be based on applying differential geometry, computer science and computer graphics to studying the conformations, chemistry and interactions of proteins and drugs. The protein conformation comparison method will compute a path in molecular conformational space that connects two given conformations of a protein, or of two closely related proteins. This will help in the understanding of protein conformational transitions and structural changes due to site-specific mutagenesis experiments or natural evolution and variation, including point mutation diseases. The small molecule comparison method should help in rational drug design.