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

分子自组装是指分子通过非共价键自发地结合成稳定的、结构明确的复合物。 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将使用一种逆向方法，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。这些蛋白质将在计算上对接在一起，然后被视为一个界面侧链突变和重新包装的方式类似于一个良好折叠的蛋白质的核心。目标是选择特定的氨基酸，在突变后，将提供驱动复合物形成的物理化学相互作用。为了补充这些努力，将采用强大的实验技术来筛选突变候选蛋白的组合文库，以获得以高亲和力结合靶蛋白的突变候选蛋白。这个职业项目将有助于PI作为教师学者的发展，因为它结合了本科生，研究生，研究生和初中/高中学生的教育计划。除了上述研究工作外，正在开发一个实验室课程，旨在使学生牢固理解作为法医学新兴领域基础的化学和生物学原理。这项研究的教育影响体现在PI与圣地亚哥县机构合作开发一系列基于调查的实验室模块的试点项目中，来自服务不足地区的学生探索法医学中使用的基本方法。这一教育目标的优点是向青年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.