Advanced image processing software for membrane protein structure determination

描述（由申请人提供）：我们将开发一个软件系统，以提高膜蛋白结构测定的速度、效率和分辨率。虽然膜蛋白构成了大多数药物靶点，但缺乏人类膜蛋白的结构信息给基于结构的药物设计带来了障碍。传统的x射线或核磁共振方法测定蛋白质结构在应用于膜蛋白时面临严峻的挑战。电子晶体学使用高分辨率电子显微镜来成像脂质膜重构膜蛋白的二维晶体。不幸的是，即使使用电子晶体学，药物设计所需的结构分辨率在样品制备和图像处理方面也遇到了困难。我们建议开发一种新的图像处理系统，通过包括最近开发的几种数学算法，使电子晶体图像的结构重建现代化，从而提高重建的分辨率。我们的系统将自动处理，这将使有竞争力的处理时间。最重要的是，我们的新算法将大大提高该方法的效率，因为它能够处理以前无法使用的图像。第一阶段的工作将通过在命令行级别实现三个软件扩展并演示改进的分辨率来证明可行性。第二阶段将进一步细化数学模块，并将其实现为用户友好的GUI。该软件将成为EON Structures实现高通量、高分辨率膜蛋白结构测定的技术基础，用于药物研究和基于结构的药物设计。膜蛋白是目前药物开发的主要靶点。基于结构的药物设计是药物开发中最有力的方法之一，但膜蛋白的结构一直非常难以生产。我们将测试计算机图像处理的新方法，这将使我们大大提高确定膜蛋白三维结构的速度和分辨率。该项目将通过新软件的直接销售和许可产生重大的商业影响，并使我们能够使用这些工具为制药公司进行基于合同的膜蛋白结构测定。

DESCRIPTION (provided by applicant): We will develop a software system to improve the speed, efficiency and resolution of membrane protein structure determination. While membrane proteins comprise the majority of pharmaceutical drug targets, lack of structural information for human membrane proteins poses a roadblock for structure-based drug design. Conventional protein structure determination by X-ray or NMR methods faces serious challenges when applied to membrane proteins. Electron crystallography instead uses high-resolution electron microscopes to image two-dimensional crystals of lipid membrane-reconstituted membrane proteins. Unfortunately, even with electron crystallography the structure resolution required for drug design has met with difficulties in sample preparation and image processing. We propose to develop a new image processing system that will modernize the structure reconstruction from electron crystallography images by including several recently developed mathematical algorithms, thereby improving the resolution of the reconstructions. Our system will automate the processing, which will enable competitive processing times. And, most importantly, our new algorithms will greatly improve the efficiency of the method, by being able to process images that previously could not be used. Phase I work will prove feasibility by implementing three software extensions at command line level and demonstrating improved resolution. Phase II will further refine the mathematic modules and implement them is a user friendly GUI. This software will be the technological basis for EON Structures to enable high-throughput, high-resolution membrane protein structure determination for pharmaceutical research and structure-based drug design. Membrane proteins represent the main target for drugs currently under pharmaceutical development. Structural based drug design is one of the most powerful methods of drug development, but structures for membrane proteins have been extremely difficult to produce. We will test new methods for computer image processing which should allow us to greatly advance the speed and resolution of determining the 3D structure of membrane proteins. This project will have significant commercial impact both through direct sale and license of the new software, and by enabling our use of these tools for contract based membrane protein structure determination for pharmaceutical companies.