CAREER: Computational Modeling of Protein Evolvability

虽然人们认识到蛋白质的分子进化是物种进化所不可或缺的，但蛋白质进化的物理机制和促进进化的蛋白质的物理性质还没有被很好地理解。这个职业项目的目标是通过开发和应用新的理论模型来解决这些问题，这些模型能够快速和准确地捕捉与酶功能进化相关的基本物理和化学。该方法将特别涉及模拟突变对天然蛋白质折叠稳定性的影响以及突变对催化效率的影响。这些和其他理论工具在信息模型系统中的应用将形成发现与分子进化相关的物理化学特征的基础。这些特征的例子包括补偿突变的物理机制，以及蛋白质稳定性和动力学在促进向新的酶活动过渡方面的作用。这个职业项目代表了一种综合的多学科教育和研究方法，重点是使用化学和物理定律来解释和预测生物学中的基本进化过程。该项目产生的分子进化的新方法和新的物理理解将对包括蛋白质工程和设计、定向进化和纳米技术在内的各种领域产生直接影响。除了这项研究的影响外，教育目标还将通过培训本科生和研究生从定量的角度处理生物问题来影响未来的科学家。这一目标将通过开设一门新的化学生物学本科课程和一门新的生物物理化学研究生课程来部分实现。此外，这个项目将包括开发一个新的互动软件包，该软件包将进一步确立学生将量化思维应用于生物问题的价值。该软件将通过允许学生探索蛋白质的物理性质和蛋白质的生物功能之间的联系来实现这一点。开发的教育软件将产生广泛的影响，因为它将免费分发给公众，因此将在国内和国际上供大学使用。

While it is recognized that the molecular evolution of proteins is integral to the evolution of species, the physical mechanisms underlying protein evolution and the physical properties of proteins that facilitate evolution are not well understood. The objective of this CAREER project is to address these questions through the development and application of new theoretical models that rapidly and accurately capture the essential physics and chemistry relevant to the evolution of enzyme function. The approach will specifically involve modeling the effects of mutations on the stability of a native protein fold as well as the effects of mutation on catalytic efficiency. The application of these and other theoretical tools to informative model systems will form the basis for discovering physical-chemical features associated with molecular evolution. Examples of these features include the physical mechanisms underlying compensatory mutations as well as the role of protein stability and dynamics in facilitating transitions to new enzymatic activities.This CAREER project represents an integrated and multidisciplinary educational and research approach, focused on using the laws of chemistry and physics to explain and predict fundamental evolutionary processes in biology. The new methods and new physical understanding of molecular evolution resulting from this project will have direct implications for a variety of fields including protein engineering and design, directed evolution, and nanotechnology. In addition to the impact of the research, the educational goals will impact future scientists by training undergraduate and graduate students to approach biological questions from a quantitative perspective. This objective will be partially realized through the development of a new undergraduate course in chemical biology and a new graduate level course in biophysical chemistry. In addition, this project will involve the development of a new interactive software package that will further establish, for students, the value of applying quantitative thinking to biological questions. The software will do this by allowing students to explore the connection between the physical properties of proteins and the biological function of proteins. The developed educational software will have a broad impact as it will be distributed freely to the public and will therefore be available to universities nationally and internationally.