CAREER: Computational Approaches to Understanding Membrane Protein Energetics and Function

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。位于细胞膜中的蛋白质发挥着重要的结构作用，但它们也对细胞感知和响应环境刺激的能力至关重要。例如，离子通道随着膜电压或膜张力的变化而开放，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是至关重要的。这个项目的研究目标是建立和使用计算工具来阐明膜蛋白与膜相互作用的性质。这类工具对于了解蛋白质从内质网(ER)到质膜的折叠和运输以及了解在膜上经历构象重排的蛋白质的功能特性是必要的。目前，对带电螺旋肽的分子模拟预测的膜插入能比实验得出的要大得多。因此，需要新的计算方法来找出这些差异的根源并帮助解决它们。这个职业项目将(A)允许开发一种快速、连续的方法来计算膜蛋白质的插入能量和相对稳定性，(B)使用这个计算模型来预测从膜上提取蛋白质的能量和动力学，并将这些速率与从内质网中提取的体内实验进行比较，以及(C)研究电压变化如何操纵电压传感器蛋白质来控制它们的行为。膜插入模型将被打包成一个可免费获得的、跨平台的Java程序，该程序具有直观的图形界面，用于执行膜蛋白质能量计算。这一职业计划的教育部分包括继续开发一门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。这个项目将使研究人员和他的同事能够编写一本本科教科书。本科课程和教科书将培训未来的生物学家了解生物科学中的尖端技术所需的数学知识。此外，这项研究计划包括为高中学生开发基础数学暑期课程，这些学生是科学方面代表性不足的少数族裔成员，并参加了从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，并鼓励他们进入高等教育机构并取得成功。

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.