Fine tuning of protein functional atomistic dynamics in molecular evolution and cellular processes

蛋白质是细胞的基本构件之一，在细胞内进行过程是必不可少的。这项研究的发现将为了解蛋白质的运动或动力学以及它们与其他分子的相互作用如何影响蛋白质功能提供新的基本理解。更好地了解蛋白质的功能可以帮助设计用于生物技术应用的新的蛋白质催化剂，并有助于更好地理解蛋白质功能障碍如何导致疾病。这项研究还将产生新的计算工具，包括新的软件，这些工具将帮助其他人进行研究和开发新技术。这项研究跨越了许多学科，包括化学、生物、物理、数学和计算机科学，为培养各个层次的学生提供了一个极好的机会。更具体地说，这项研究将对佐治亚州立大学学生的科学培训产生更广泛的影响，重点是更好地为少数族裔学生进入研究生院做好准备。佐治亚州立大学是佐治亚州最大和最多样化的研究密集型大学，提供了一个独特的机会，让多样化的学生群体和代表不足的少数群体参与到科学和工程领域。学生将具备成功过渡到化学和生物医学博士课程所需的研究经验、基础知识和专业技能。此外，该项目将通过佐治亚州立大学成熟的项目向更大的社区提供服务。蛋白质构象运动在许多细胞过程中指导分子识别、酶催化和变构调节。构象动力学是许多细胞过程微调的基础，包括瞬时蛋白质-蛋白质相互作用、信号转导和基因调控，以响应生化过程和细胞条件的变化。放松对控制其中一个或多个过程的动力学的调控，可能会导致细胞功能异常。尽管人们对阐明复杂的结构-动力学-功能关系进行了深入的研究，但蛋白质功能是如何进化和调控的仍然知之甚少。这项研究的目标是利用在不同底物结合和序列条件下进行的大规模计算机模拟，建立蛋白质功能可控调制的动态联系。具体地说，这项研究将确定蛋白质功能的各种修饰，包括催化活性的获得和丧失，是如何通过人类亲环素家族的进化实现的，并建立人类Pin1中依赖序列的变构机制的完整模型。此外，将开发创新和高效的计算方法，从大型模拟数据中识别蛋白质中的关键变构残基。将获得变构信号如何在蛋白质残基-残基相互作用网络中微观传播的一般原理，补充了为宏观理解变构调节而建立的热力学模型。这项研究将对蛋白质动力学在细胞过程中的识别、催化和变构调节中的作用提供深入的见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Proteins are one of the basic cellular building blocks and are essential for carrying out processes inside cells. The findings of this research will provide new basic understanding of how the movement or dynamics of proteins and their interactions of other molecules affects protein function. Better understanding of protein function could help in the design of new protein catalysts for biotechnology applications and well as lead to a greater understanding of how protein disfunction contributes to disease. The research will also produce new computational tools, including new software, that will assist others in their research and in developing new technology. The research cuts across many disciplines, including chemistry, biology, physics, mathematics, and computer science, and provides an excellent opportunity to train students at all levels. More specifically, the research will have a broader impact on the scientific training of students at Georgia State University, with focus on better preparing underrepresented minority students for graduate school. Georgia State University is the largest and most diverse research-intensive university in Georgia, providing a unique opportunity to engage a diverse student body and underrepresented minority groups in science and engineering. Students will be equipped with research experiences, fundamental knowledge, and professional skills that are required to successfully transition to doctoral programs in chemical and biomedical sciences. Additionally, the project will provide outreach to a larger community through well-established programs at Georgia State University.Protein conformational motions direct molecular recognition, enzyme catalysis, and allosteric regulation in many cellular processes. Conformational dynamics underlies the fine tuning of many cellular processes, including transient protein-protein interactions, signal transduction, and gene regulation in response to biochemical processes and changes in cellular conditions. Deregulation of the dynamics controlling one or more of these processes can lead to aberrant cellular function. Despite intensive studies on elucidating the complex structure-dynamics-function relationship, how protein function has evolved and is regulated remain poorly understood. The goal of the research is to establish the dynamical link for controllable modulations of function in proteins using large-scale computer simulations performed under distinct substrate-binding and sequence conditions. Specifically, the research will determine how various modifications of protein function, including gain and loss of catalytic activity, are achieved through evolution in the family of human cyclophilins and establish a complete model of the sequence dependent allosteric mechanism in human Pin1. Additionally, innovative and efficient computational methods will be developed to identify key allosteric residues in proteins from large simulation data. General principles of how allosteric signals microscopically propagate within a network of protein residue-residue interactions will be obtained, complementing the well-established thermodynamic models for macroscopic understanding of allosteric regulation. The research will provide deep insights into the role of protein dynamics in recognition, catalysis, and allosteric regulation in cellular processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.