CAREER: Computational Approaches to Understanding Membrane Protein Energetics and Function

职业：理解膜蛋白能量学和功能的计算方法

• 批准号: 0845286
• 负责人: Jeffrey Brodsky
• 金额: $ 93.23万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0845286&HistoricalAwards=false
• 关键词: CAREER; Computational; Approaches; Understanding; Membrane

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).Proteins that reside in the cell membrane play important structural roles, but they are also critical to the cell's ability to sense and respond to environmental stimuli. For instance, ion channels open in response to changes in membrane voltage or membrane tension to permit the flow of molecules into and out of the cell. Knowledge of how proteins interact with the membrane is essential to our understanding of these functions. The research goal of this project is to build and use computational tools for elucidating the nature of membrane proteins' interactions with the membrane. Such tools are needed to understand the folding and trafficking of proteins from the endoplasmic reticulum (ER) to the plasma membrane and to understand the functional properties of proteins that undergo conformational rearrangements in the membrane. Currently, molecular simulations of charged helical peptides predict membrane insertion energies that are much larger than those derived from experiment. Therefore, new computational approaches are needed to pinpoint the source of these differences and help to resolve them. This CAREER project will (a) allow for the development of a fast, continuum based method for calculating the insertion energies and relative stabilities of membrane proteins, (b) use this computational model to predict the energy and kinetics of protein extraction from the membrane and compare these rates with in vivo extraction experiments from the ER, and (c) study how voltage changes manipulate voltage-sensor proteins to control their behavior. The membrane insertion model will be packaged into a freely available, cross-platform JAVA program with an intuitive graphical interface for carrying out membrane protein energetic calculations.Broader Impacts. The educational component of this CAREER project involves continued development of a new mathematical biology course that introduces upper division undergraduate students to mathematical concepts that have greatly impacted biology. This project will enable the writing of an undergraduate textbook by the investigator and his colleagues. The undergraduate course and textbook will train future biologists in the mathematics needed to understand cutting-edge technologies in the biological sciences. Additionally, this research program includes the development of a summer course in basic mathematics for high school students who are members of minorities under-represented in science and who are enrolled in the School-to-Career Teen Program (Pittsburgh, PA). It will permit continued math and science education for these high school students and encourage them to attend and succeed at post-secondary educational institutions.

该奖项是根据 2009 年美国复苏和再投资法案（公法 111-5）资助的。细胞膜中的蛋白质发挥着重要的结构作用，但它们对于细胞感知和响应环境刺激的能力也至关重要。例如，离子通道响应膜电压或膜张力的变化而打开，以允许分子流入和流出细胞。了解蛋白质如何与膜相互作用对于我们理解这些功能至关重要。该项目的研究目标是构建并使用计算工具来阐明膜蛋白与膜相互作用的性质。需要此类工具来了解蛋白质从内质网 (ER) 到质膜的折叠和运输，并了解在膜中经历构象重排的蛋白质的功能特性。目前，带电螺旋肽的分子模拟预测的膜插入能量比实验得出的能量大得多。因此，需要新的计算方法来查明这些差异的根源并帮助解决它们。该职业项目将（a）开发一种快速、连续的方法来计算膜蛋白的插入能量和相对稳定性，（b）使用该计算模型来预测从膜中提取蛋白质的能量和动力学，并将这些速率与内质网的体内提取实验进行比较，以及（c）研究电压变化如何操纵电压传感器蛋白质来控制其行为。膜插入模型将被打包成一个免费的、跨平台的JAVA程序，具有直观的图形界面，用于进行膜蛋白能量计算。更广泛的影响。该职业项目的教育部分涉及持续开发新的数学生物学课程，向高年级本科生介绍对生物学产生重大影响的数学概念。该项目将使研究者和他的同事能够编写本科生教科书。本科课程和教科书将为未来的生物学家提供理解生物科学尖端技术所需的数学知识。此外，该研究计划还包括为高中生开设基础数学暑期课程，这些高中生属于科学领域代表性不足的少数群体，并且参加了学校到职业青少年计划（宾夕法尼亚州匹兹堡）。它将允许这些高中生继续接受数学和科学教育，并鼓励他们进入专上教育机构并取得成功。