Theoretical Studies of Membrane Proteins

膜蛋白的理论研究

• 批准号: 0416708
• 负责人: Barry Honig
• 金额: $ 78.93万
• 依托单位: Columbia University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0416708&HistoricalAwards=false
• 关键词: Theoretical; Studies; Membrane; Proteins; Theoretical; Studies; Membrane; Proteins

The objective of this project is to develop and test methods for the homology modeling of membrane proteins. The homology modeling of soluble proteins and membrane proteins are areas that have developed quite independently, in part because of the vast difference in the quantity of structural information that has been available for both. In the case of soluble proteins the development and validation of computational tools have benefited from the availability of a large number of three-dimensional structures. For example, it has been possible to build models and then test them either in blind prediction as in the CASP experiment (Critical Assessment of Structure Prediction) or by comparing "predictions" of known structures to experimental structures in an unbiased fashion. The increasing number of membrane protein structures that are becoming available suggests that a similar kind of validation is now possible for this class of proteins. The central goal of this research is the development of a new battery of software tools that will allow researchers to build models and to evaluate them in an unbiased fashion. A key element of the research is the construction of models for membrane proteins of known structure based on the coordinates of related proteins. The ability of different energy functions to distinguish the decoy from the native conformation will be tested. The ability to predict the correct orientation of the protein with respect to the lipid bilayer will also be tested. The modeling approach to be taken is based on methods that have been developed in the PI's lab in studies of soluble proteins. These include novel tools to predict the conformation of amino acid side chains on afixed backbone, novel loop prediction methods and a new model building program. A key element of the research is the use of physical chemical-based energy criteria to evaluate the relative conformational energies of different models for a given protein. Refined energetic methods suitable for membrane proteins will be developed as the research progresses and will be combined with criteria for helix packing derived from the growing database of membrane protein structures. The broader impact of the research includes the development of software tools that are likely to be widely used in basic research and in a variety of technological applications. The research will also provide a platform for the training of women and minority scientists, a tradition in the lab for some time.

该项目的目的是开发和测试膜蛋白同源性建模的方法。可溶性蛋白和膜蛋白的同源性建模是已经独立发展的区域，部分原因是两者都可以使用的结构信息的数量差异很大。在可溶性蛋白的情况下，计算工具的开发和验证已受益于大量三维结构的可用性。例如，可以像CASP实验（对结构预测的批判性评估）或以公正的方式将已知结构的“预测”与实验结构进行比较，可以构建模型，然后在盲目的预测中测试它们。越来越多的膜蛋白结构越来越多地表明，现在这类蛋白质现在可以进行类似的验证。这项研究的核心目标是开发新的软件工具，这些软件工具将使研究人员能够建立模型并以公正的方式进行评估。该研究的一个关键要素是基于相关蛋白的坐标的已知结构膜蛋白模型的构建。将测试不同能量功能区分诱饵与天然构象的能力。还将测试预测蛋白质相对于脂质双层的正确取向的能力。要采用的建模方法基于在可溶性蛋白研究中PI实验室中开发的方法。 其中包括预测氨基酸侧链在后链链，新型环路预测方法和新的模型构建程序上的构象的新颖工具。 该研究的一个关键要素是使用基于物理化学的能量标准来评估给定蛋白质不同模型的相对构象能。随着研究的进行，将开发适合膜蛋白的精制能量方法，并将与源自不断增长的膜蛋白结构数据库得出的螺旋填料的标准结合使用。该研究的更广泛影响包括开发可能在基础研究和各种技术应用中广泛使用的软件工具。这项研究还将为培训妇女和少数族裔科学家的培训提供一个平台，这是实验室的传统。