Development of New Methods and Software for X-ray Crystallography

9876668摘要x射线晶体学是测定大分子三维结构的有力工具。这些结构信息对于理解蛋白质和DNA的生化特性和生物学功能非常有用。目前用于生物大分子x射线结构测定的方法主要有多重同构替代法（MIR）、多波长异常衍射法（MAD）和分子替代法（MR）。本项目将重点开发分子替代法的新技术和计算机软件。磁共振方法以同源蛋白的原子模型为起点求解新的蛋白质结构。计算旋转和平移函数，使搜索模型在晶体中正确定位。蛋白质晶体学和核磁共振的显著成功已经导致许多独特的蛋白质结构（折叠）的阐明，这样一个新的感兴趣的蛋白质往往显示出一定程度的氨基酸序列同源性的蛋白质已知结构。到目前为止，MR方法在氨基酸序列同源性高的情况下效果最好，但通常在较低同源性的情况下只有有限的成功。近年来，许多新技术被开发出来，试图提高这一重要的蛋白质结构测定方法的能力。为了使核磁共振方法更加强大，还需要进一步的发展，而且是可能的。这一领域的成功发展可以提高整个晶体学界的生产力。当前研究项目的具体目标是开发新技术：1 .推导更合适的搜索原子模型；2. 获得较好的旋转函数结果；3. 获得较好的翻译函数结果；4. 旋转和平移功能搜索更好的结合和自动化。这个项目的总体目标是开发和维护一个新的和用户友好的计算机软件包，其中包含了这些新技术。该软件将提供给整个晶体学界。

9876668AbstractX-ray crystallography is a powerful tool for determining the three-dimensional structures of macromolecules. Such structural information is extremely useful in understanding the biochemical properties and the biological functions of proteins and DNA. Three major methods are currently available for X-ray structure determination of biological macromolecules multiple isomorphous replacement (MIR), multiple-wavelength anomalous diffraction (MAD), and molecular replacement (MR). This projectl will focus on developing new techniques and computer software for the molecular replacement method. The MR method solves new protein structures using the atomic model of a homologous protein as the starting point. Rotation and translation functions are calculated to correctly orient and position this search model in the crystal. The remarkable success of protein crystallography and NMR has led to the elucidation of many unique protein structures protein folds), such that a new protein of interest oftentimes displays some degree of amino acid sequence homology to a protein of known structure. The MR method so far works best when the amino acid sequence homology is high, but generally has had only limited success in the more common cases of lower homology. Many new techniques have been developed in recent years in attempts to enhance the capability of this important method of protein structure determination. Further developments are still needed, and possible, to make the MR method even more powerful. Successful developments in this area can increase the productivity of the entire crystallography community. The specific aims of the current research project are the development of new techniques for - I. deriving more appropriate search atomic models; 2. obtaining better rotation function results; 3. obtaining better translation function results; 4. better combination and automation of the rotation and translation function searches. The overall goal of this project is the development and maintenance of a new and user-friendly computer software package that incorporates these new techniques. This software will be made available to the entire crystallography community.