Novel Algorithms for Crystallographic Computing

晶体学计算的新算法

• 批准号: 6879498
• 负责人: Nikolaos Sahinidis
• 金额: $ 40.5万
• 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/6879498
• 关键词: X ray crystallography; bioengineering /biomedical engineering; bioimaging /biomedical imaging; computational biology; computer program /software; computer system design /evaluation; macromolecule; mathematical model; method development; model design /development; molecular shape; protein structure; statistics /biometry; structural biology; three dimensional imaging /topography

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）：自十九世纪中期以来，晶体的X射线衍射数据的分析已广泛用于确定分子结构和性质。虽然该方法在世界范围内几乎常规使用，但识别最适合衍射数据的三维结构通常是一个重大挑战。尤其一个关键的障碍是仅通过强度测量来识别衍射射线的相位。这个问题在晶体学中被称为“相问题”，其解决方案是推进大分子晶体学和结构生物学前沿的主要障碍。 该项目的主要目标是开发解决晶体计算中的相位问题的系统方法。为了实现这一目标，我们计划： (a) 开发新颖的数学模型，用于通过单晶 X 射线衍射测量确定三维晶体结构； (b) 设计数学优化算法以可靠且有效的方式求解上述模型，从而增加可处理结构的尺寸； (c) 开发并向研究界提供实施上述模型和算法的计算系统； (d) 应用已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。该项目将建立在首席研究员最近首创的一种新颖算法的基础上，以解决合作团队已证明能够解开生物分子结构的模型。 该项目更广泛的影响包括指导研究生和博士后学员、将研究成果整合到生物信息学课程中，以及通过实施该项目成果的在线软件进行广泛传播。拟议的工作有望为新一代晶体学计算系统奠定基础，该系统将揭示对理解生命、材料科学和药物设计重要的结构。对社会的长期影响可能是巨大的，因为该项目可能会产生能够破译生命秘密的方法，并在新药的开发中发挥关键作用。