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

分子进化和细胞过程中蛋白质功能原子动力学的微调

• 批准号: 2018144
• 负责人: Donald Hamelberg
• 金额: $ 97.15万
• 依托单位: Georgia State University Research Foundation, Inc.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2018144&HistoricalAwards=false
• 关键词: Fine; tuning; protein; functional; atomistic

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.

蛋白质是基本的细胞构建块之一，对于在细胞内进行过程至关重要。 这项研究的发现将为蛋白质的运动或动力学及其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。 更好地了解蛋白质功能有助于设计新的蛋白质催化剂用于生物技术应用，并有助于更好地了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，这将有助于其他人的研究和开发新技术。该研究跨越许多学科，包括化学，生物学，物理学，数学和计算机科学，并提供了一个很好的机会，培养各级学生。更具体地说，这项研究将对格鲁吉亚州立大学学生的科学培训产生更广泛的影响，重点是更好地为代表性不足的少数民族学生准备研究生院。格鲁吉亚州立大学是格鲁吉亚最大，最多样化的研究密集型大学，提供了一个独特的机会，从事多元化的学生团体和代表性不足的少数群体在科学和工程。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，该项目将通过在格鲁吉亚州立大学的完善的项目提供外展到更大的社区。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、信号转导和响应于生化过程和细胞条件变化的基因调控。控制这些过程中的一个或多个的动力学的失调可导致异常的细胞功能。尽管深入研究阐明了复杂的结构-动力学-功能关系，但蛋白质功能如何进化和调节仍然知之甚少。这项研究的目标是建立动态链接的可控调制功能的蛋白质使用大规模的计算机模拟不同的底物结合和序列条件下进行。具体而言，该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Pin 1序列依赖性变构机制的完整模型。此外，创新和有效的计算方法将被开发，以确定关键的变构残基的蛋白质从大型模拟数据。将获得变构信号如何在蛋白质残基-残基相互作用网络内微观传播的一般原理，补充了宏观理解变构调节的成熟热力学模型。该研究将为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。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

p53 Is Potentially Regulated by Cyclophilin D in the Triple-Proline Loop of the DNA Binding Domain

p53 可能受 DNA 结合域三脯氨酸环中的亲环蛋白 D 调节

• DOI: 10.1021/acs.biochem.0c00946
• 发表时间: 2021
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Kumutima, Jacques;Yao, Xin-Qiu;Hamelberg, Donald
• 通讯作者: Hamelberg, Donald

Subsets of adjacent nodes (SOAN): a fast method for computing suboptimal paths in protein dynamic networks

• DOI: 10.1080/00268976.2021.1893847
• 发表时间: 2021-03
• 期刊: Molecular Physics
• 影响因子: 1.7
• 作者: T. Dodd;Xin-Qiu Yao;D. Hamelberg;I. Ivanov

Computational benchmarking of putative KIFC1 inhibitors

• DOI: 10.1002/med.21926
• 发表时间: 2022-09
• 期刊: Medicinal Research Reviews
• 影响因子: 13.3
• 作者: Nivya Sharma;Dani Setiawan;D. Hamelberg;Rishikesh Narayan;R. Aneja