CAREER: Combined Computational and Experimental Approaches for the Design of Protein-Protein Interactions

分子自组装是分子通过非共价键连接成稳定的、结构明确的络合物的自发结合。这个职业项目的目标是了解并最终控制驱动蛋白质自组装的力量。为了实现这一目标，PI将使用一种反向方法，将尖端的计算对接方法与先进的蛋白质设计算法相结合，以驱动先前单体蛋白质的自组装。这些蛋白质将通过计算对接在一起，然后被视为界面侧链发生突变并以类似于折叠良好的蛋白质核心的方式重新包装的蛋白质。我们的目标是选择特定的氨基酸，这些氨基酸在突变时将提供驱动复合体形成的物理化学相互作用。为了补充这些努力，将使用强大的实验技术来筛选与目标蛋白高亲和力结合的突变候选蛋白的组合文库。这一职业项目将有助于国际学生协会作为教师-学者的发展，因为它包括本科生、研究生、研究生和初中生的教育方案。除上述研究工作外，正在开发一门实验室课程，旨在使学生对构成新兴法医科学领域基础的化学和生物原理有一个确切的了解。这项研究的教育影响体现在这样一个事实上，即PI正在与圣地亚哥县机构合作，为一个试点项目开发一系列以探究为基础的实验室模块，在该项目中，来自服务不足地区的学生将探索法医学中使用的基本方法。这一教育目标的优点是向年轻人灌输终身学习的愿望，从而取得成功。

Molecular self-assembly is the spontaneous association of molecules into stable, structurally well-defined complexes joined by noncovalent bonds. The objective of this CAREER project is to understand and ultimately control the forces that drive protein self-assembly. To achieve this aim, the PI will use an inverse approach that combines cutting-edge computational docking methods with advanced protein design algorithms to drive the self-assembly of previously monomeric proteins. The proteins will be computationally docked together and then treated as one where interfacial side chains are mutated and repacked in a manner analogous to the core of a well-folded protein. The goal is to select the specific amino acids that, upon mutation, will provide the physical chemical interactions that drive complex formation. To complement these efforts powerful experimental techniques will be employed that function to screen combinatorial libraries of mutant candidate proteins for those that bind target proteins with high affinity. This CAREER project will contribute to the development of the PI as a teacher-scholar as it incorporates educational programs for undergraduate, graduate, postgraduate and middle/high school students. In addition to the above research efforts a laboratory course is being developed that is meant to provide students with a firm understanding of the chemical and biological principles that underlie the emerging field of forensics science. The educational impact of this research is exemplified by the fact that the PI is working collaboratively with San Diego County agencies to develop a series of inquiry-based lab modules for a pilot program in which students from underserved areas explore basic methods used in forensic science. The merit of this educational aim is to instill in youth the lifelong desire to learn and thereby succeed.