Understanding the structural basis of transmembrane association with a multidisciplinary strategy

该奖项来自化学学部生命过程化学项目，资助亚历山德罗·塞内斯和亚伦·霍斯金斯教授。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%。它们负责多种重要的细胞功能，如：运输、信号传导、粘附、发育和许多调节过程。本研究项目探讨导致跨膜稳定性和特定膜蛋白功能的因素。塞内斯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（以及实践经验）的各种主题。本课程的目标是建立对计算生物学的认识和兴趣。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。结构中心点是一种预测GASright二聚体结构的计算方法，具有较高的置信度和精度。GASright最著名的是糖蛋白A二聚体（GpA）的折叠，这是TM螺旋结合的主要模型系统。GASright的名称来源于其螺旋之间的右手交角（接近-40°），以及其界面上的特征小氨基酸（Gly, Ala, Ser: GAS），它们排列成GxxxG和GxxxG样图案（GxxxA， AxxxG等）。该计算方法用于从数千个跨膜螺旋蛋白序列中识别GASright候选序列，以进行高通量实验分析。所得到的数据产生了GASright结合能量学的定量模型，然后在体外对一小组选定的蛋白质进行测试。总的来说，该研究代表了跨膜螺旋关联的大规模结构分析，可能产生GASright的稳定性和特异性的定量模型。

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.