Understanding the structural basis of transmembrane association with a multidisciplinary strategy

该奖项来自化学系生命过程计划的化学，为Alessandro Senes和Aaron霍斯金斯教授提供资金。该项目研究了稳定位于细胞膜上的蛋白质的因素。 其中一些蛋白质被称为跨膜蛋白，因为它们穿过整个细胞膜。 膜蛋白占所有蛋白质的20-40%。 它们负责各种重要的细胞功能，例如：运输，信号传导，粘附，发育和许多调节过程。本研究项目探讨了导致跨膜稳定性的因素和特定膜蛋白的功能。 Senes和霍斯金斯教授设计的课程提供了生物信息学的介绍，包括生物化学（基因组学，蛋白质组学，系统生物学，结构/预测）和计算方法（和实践经验）的各种主题。 本课程的目标是建立意识和兴趣的计算生物学。 该团队还为高中生开发了一个交互式计算生物学模块，专注于生物学的定量方面以及将计算与实验相结合的重要性。该项目涉及计算结构预测、高通量相互作用研究以及单分子生物物理学。结构中心是一种计算方法，可以预测GASright二聚体的结构，具有良好的置信度和精度。GASright最为人所知的是血型糖蛋白A二聚体（GpA）的折叠，这是TM螺旋缔合的主要模型系统。GASright的名称来源于螺旋之间的右旋交叉角（接近-40°），以及其界面处的特征性小氨基酸（Gly，Ala，Ser：GAS），它们排列形成GxxxG和GxxxG样模式（GxxxA，AxxxG等）。 计算方法被用来确定GASright候选人之间的跨膜螺旋的蛋白质序列的高通量实验分析的数千人。由此产生的数据产生的GASright关联能量学的定量模型，然后在体外测试一小组选定的蛋白质。总的来说，这项研究代表了一个大规模的基于结构的跨膜螺旋关联分析，可能会产生一个定量模型的稳定性和特异性的GASright。

This award from the Chemistry of Life Processes Program in the Chemistry Division funds Professors Alessandro Senes and Aaron Hoskins. The project investigates the factors that stabilize proteins located in the membrane of a cell. Some of these proteins are called transmembrane proteins since they cross the entire cell membrane. Membrane proteins represent 20-40% of all proteins. They are responsible for a variety of vital cellular functions, such as: transport, signaling, adhesion, development, and many regulatory processes. This research project examines the factors that lead to transmembrane stability and the function of specific membrane proteins. Professors Senes and Hoskins design courses that offer an introduction to bioinformatics, including a variety of topics in biochemistry (genomics, proteomics, systems biology, structure/prediction) and computational methods (and hand-on experience). The objective of this course is to create awareness and interest in computational biology. The team also develops an interactive computational biology module for high-school students focused on the quantitative aspects of biology and the importance of integrating computation with experiments. This project involves computational structure prediction, and high-throughput interaction studies, as well as single-molecule biophysics. The structural centerpiece is a computational method that can predict the structure of GASright dimers with good confidence and precision. GASright is best known as the fold of the glycophorin A dimer (GpA), the major model system for TM helix association. The name GASright originates from the right-handed crossing angle between the helices (near -40°), and from the characteristic small amino acids (Gly, Ala, Ser: GAS) at its interface, which are arranged to form GxxxG and GxxxG-like patterns (GxxxA, AxxxG, etc.). The computational method is used to identify GASright candidates among thousands of protein sequences of transmembrane helices for high-throughput experimental analysis. The resulting data produces a quantitative model of GASright association energetics, which is then tested in vitro on a small set of selected proteins. Overall, the research represents a large-scale structure-based analysis of transmembrane helix association that may produce a quantitative model of stability and specificity for GASright.