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。驻留在细胞膜上的蛋白质起着重要的结构作用，但它们对细胞感知和响应环境刺激的能力也至关重要。例如，离子通道响应于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。蛋白质如何与膜相互作用的知识对于我们理解这些功能至关重要。本计画的研究目标是建立并使用计算工具来阐明膜蛋白与膜相互作用的本质。需要这样的工具来理解蛋白质从内质网（ER）到质膜的折叠和运输，并理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远大于那些来自实验。因此，需要新的计算方法来查明这些差异的来源并帮助解决它们。该CAREER项目将（a）允许开发一种快速、基于连续介质的方法，用于计算膜蛋白的插入能和相对稳定性，（B）使用该计算模型预测膜蛋白提取的能量和动力学，并将这些速率与ER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以控制它们的行为。膜插入模型将被打包成一个免费提供的跨平台JAVA程序，该程序具有直观的图形界面，用于进行膜蛋白能量计算。这个职业生涯项目的教育部分涉及一个新的数学生物学课程，介绍上师本科生的数学概念，极大地影响了生物学的持续发展。该项目将使调查员及其同事能够编写一本本科教科书。本科课程和教科书将培养未来的生物学家在数学需要了解尖端技术在生物科学。此外，这项研究计划还包括为高中学生开发基础数学暑期课程，这些学生是科学中代表性不足的少数民族成员，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，并鼓励他们参加中学后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.