BRIGE: Predicting Allosteric Regulation Pathways from Local Elastic Moduli Calculations

这项扩大参与的工程研究启动补助金(Brige)旨在通过测量和分析蛋白质-S局部机械强度的3D地图，获得关于蛋白质变构的机制和途径的信息。变构作用涉及蛋白质结构中不同位点之间的信号传播。功能的改变可以通过配体的结合、在远处的共价修饰或突变来实现。这种点对点通信的机制还不清楚，人们对此很感兴趣，特别是因为在药物设计和蛋白质工程中必须考虑变构效应。该项目的第一部分将涉及开发一种技术，以计算作为分子在空间位置的函数的局部弹性模数，而第二部分将侧重于应用所产生的局部材料强度的3D图来理解变构机制，找到可能的变构位置，并预测变构信号通过分子的传播路径。这些结果将使社会受益，因为它提高了我们对变构及其与人体内发生的许多调节过程的联系的理解，并提供了一种创新工具，有可能彻底改变药物发现领域，用于治疗几种疾病和疾病，包括某些类型的癌症。此外，来自波多黎各和纽约市地区代表性不足群体的本科生、高中生和教师将通过暑期实习和参观S集团实验室接触到这些概念和方法，目的是扩大这些群体的学生的参与，并增加他们进入本科生和研究生科学、技术、工程和数学(STEM)课程的入学人数。

This Broadening Participation Research Initiation Grants in Engineering (BRIGE) grant aims at obtaining information on the mechanisms and pathways of allostery on proteins by measuring and analyzing a protein?s 3D map of local mechanical strength. Allostery involves the propagation of signals between sites in a protein structure. A change in function could be brought about by the binding of a ligand, covalent modification or mutation at a distant site. The mechanism of this site-to-site communication is not understood, and is of great interest, especially since allosteric effects must be considered in drug design and protein engineering. The first part of the project will involve development of a technique to calculate the local elastic moduli as a function of the position in space for a molecule, while the second part will focus on applying the resulting 3D maps of local material strength to understand the mechanisms of allostery, find the positions of possible allosteric sites and predict pathways of propagation of allosteric signals through a molecule. The results will benefit society by improving our understanding of allostery and its connection to many regulatory processes that happen in the human body, and by providing an innovative tool with the potential to revolutionize the field of drug discovery for the treatment of several conditions and diseases, including certain types of cancer. In addition, undergraduate students, and high school students and teachers from underrepresented groups in Puerto Rico and the New York City area will be exposed to the concepts and method through summer internships and visits to the group?s laboratory, with the purpose of broadening the participation of students from these groups and increasing their enrollment into undergraduate and graduate Science, Technology, Engineering and Mathematics (STEM) programs.