Novel Algorithms for Crystallographic Computing

晶体学计算的新算法

• 批准号: 7211483
• 负责人: Nikolaos Sahinidis
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211483
• 关键词: Algorithms; Bioinformatics; Biological; Classification; Communities; Computer software; Crystallography; Data; Development; Drug Design; Foundations; Generations; Goals; Lead; Life; Measurement; Mentors; Methodology; Methods; Modeling; Molecular Structure; Pharmaceutical Preparations; Phase; Play; Principal Investigator; Property; Proteins; Research; Role; Science; Societies; Solutions; Structure; Students; System; Work; X ray diffraction analysis; X-Ray Diffraction; base; frontier; macromolecule; mathematical model; novel; size; structural biology; three dimensional structure

DESCRIPTION (provided by applicant): Since the mid nineteen hundreds, analysis of X-ray diffraction data of crystals has been used extensively for the determination of molecular structure and properties. While the method is employed almost on a routine basis worldwide, it is often a major challenge to identify the three-dimensional structure that best fits the diffraction data. A key obstacle, in particular, is the identification of the phases of the diffracted rays from measurements of intensities alone. This problem is known as the "phase problem" in crystallography and its solution represents a major obstacle towards advancing the frontiers of macromolecular crystallography and structural biology. The primary goal of this project is the development of a systematic methodology for resolving the phase problem in crystallographic computing. Towards this goal, we plan to: (a) develop novel mathematical models for determining three-dimensional crystal structures from single crystal X-ray diffraction measurements; (b) devise mathematical optimization algorithms to solve the above models in a reliable and efficient way, thus increasing the size of tractable structures; (c) develop and make available to the research community a computational system implementing the above models and algorithms; and (d) apply the developed methodology to determine the three-dimensional structures of proteins and other important biological macromolecules. The project will build on a novel algorithm recently pioneered by the Principal Investigator to solve a model that has been demonstrated by the collaborating team to be capable of unraveling structures of biomolecules. The broader impacts of the project include mentoring of graduate students and postdoctoral trainees, integration of research results in a Bioinformatics course, and wide dissemination through on-line software implementing the results of this project. The proposed work promises to lay the foundations of a new generation of crystallographic computing systems that will reveal structures important in the understanding of life, materials science, and drug design. The long term impact to society could be immense as the project could lead to methodology capable of deciphering the secrets of life and playing a pivotal role in the development of new drugs.

描述（由申请人提供）：由于十九个中期，对晶体的X射线衍射数据的分析已被广泛用于测定分子结构和特性。尽管该方法几乎是在全球范围内常规的，但要确定最适合衍射数据的三维结构通常是一个主要挑战。尤其是一个关键的障碍是仅凭强度测量值来识别衍射光线的阶段。该问题被称为晶体学中的“相问题”，其溶液代表了促进大分子晶体学和结构生物学领域的主要障碍。 该项目的主要目标是开发一种系统的方法来解决晶体学计算中的相位问题。为了实现这一目标，我们计划：（a）开发新的数学模型，以确定单晶X射线衍射测量的三维晶体结构； （b）设计数学优化算法以可靠和有效的方式求解上述模型，从而增加了可拖动结构的大小； （c）开发并为研究社区提供了实施上述模型和算法的计算系统； （d）应用开发的方法来确定蛋白质和其他重要生物大分子的三维结构。该项目将建立在一种新的算法基础上，该算法最近由首席研究者率先解决，以解决合作团队已证明的模型，该模型能够揭示生物分子的结构。 该项目的更广泛的影响包括指导研究生和博士后学员，研究成果的整合生物信息学课程以及通过实施该项目结果的在线软件进行广泛的传播。拟议的工作有望奠定新一代晶体学计算系统的基础，该系统将揭示在理解生命，材料科学和药物设计中重要的结构。长期对社会的影响可能是巨大的，因为该项目可能会导致能够破译生活秘密并在新药开发中发挥关键作用的方法论。