NSF Postdoctoral Fellowship in Biology FY 2013

无序中的有序：了解本质上无序的蛋白质的构象图景蛋白质结合特定的伙伴执行诸如构建分子结构和传递分子信号等功能。传统上，蛋白质被认为具有稳定的结构，然而，近二十年的研究表明，超过三分之一的真核蛋白质含有长的非结构区域。这种本质上无序的蛋白质在一系列构象之间转换，这一行为负责它们结合多个伴侣的能力，并导致它们在细胞途径中的丰富。在某些种类的细菌抗毒素蛋白中，伸展构象和紧凑构象之间的转换直接控制应激反应途径。使用混合的计算和实验方法，PI将确定(1)特定抗毒素的构象系综，(2)每个构象的功能，以及(3)构象之间的转移率。改变抗毒素的突变？S构象系综会影响与毒素-抗毒素调控网络中其他大分子的相互作用。该项目将提供对细菌应激反应途径的新理解，并将为确定内在无序蛋白质的瞬时构象及其功能提供新的方法。PI将获得实验方法方面的培训，并扩展她的计算能力。这项工作的算法和成果将放在网上，以促进和推动该领域今后的研究。此外，PI还将指导一名夏季高中生进行一项生物信息学项目，该项目旨在研究抗毒素蛋白的无序区域。

Order within disorder: Understanding the conformational landscape of intrinsically disordered proteins Proteins bind specific partners to perform functions such as building molecular structures and transmitting molecular signals. Traditionally, proteins were understood to have a stable structure, however, research in the last twenty years has revealed that over one third of eukaryotic proteins contain long unstructured regions. Such intrinsically disordered proteins transition among an ensemble of conformations, a behavior responsible for their ability to bind multiple partners, and leading to their enrichment in cellular pathways. In certain classes of bacterial antitoxin proteins, transitions between extended and compact conformations directly control stress response pathways. Using a hybrid computational and experimental approach, the PI will determine the (1) conformational ensemble of a specific antitoxin, (2) function of each conformation, and (3) transition rates between the conformations. Mutations that modify the antitoxin?s conformational ensemble affect interaction with other macromolecules in the toxin-antitoxin regulatory network will be investigated.This project will provide new understanding of stress response pathways in bacteria and will yield novel methods for determining transient conformations of intrinsically disordered proteins and their functions. The PI will obtain training in experimental methods and expand her computational abilities. Algorithms and results of this work will be placed on the web to facilitate and advance future research in the field. Additionally, the PI will mentor a summer high school student on a bioinformatics project examining disordered regions of antitoxin proteins.