Adaptive Multi-Layer Simulations of NarK Transport Protein

NarK 转运蛋白的自适应多层模拟

• 批准号: 2153441
• 负责人: Hai Lin
• 金额: $ 49.7万
• 依托单位: University of Colorado at Denver-Downtown Campus
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2153441&HistoricalAwards=false
• 关键词: Adaptive; Multi; Layer; Simulations; NarK

With funding from the Chemical Theory, Models and Computational Methods program in the Division of Chemistry, Hai Lin and Emilie Guidez of the University of Colorado-Denver will develop and apply novel computational algorithms to study how ions are transported through the membrane protein NarK. The NarK protein imports nitrate (a mineral form of the essential element nitrogen) into the cell and exports nitrite (a metabolite that can be toxic in high concentrations) out of the cell. However, the mechanism of the NarK protein remains poorly understood. Accurate and efficient computer modeling and simulations are highly desired to provide critical insights. Lin and Guidez will formulate new multiscale algorithms that seamlessly combine quantum and classical modeling techniques, and employing these algorithms, their research groups will set forth to unearth the atomistic details on how NarK helps the ions travel across the cell membranes. This collaborative research has the potential to fundamentally advance understanding of nutrient uptake by membrane transporters and, consequently, in the longer term, potentially assist in the development of novel therapies for diseases related to these protein malfunctions. The University of Colorado-Denver is both a Hispanic-Serving Institution (HSI) and an Asian American Native American Pacific Islander-Serving Institution. Lin and Guidez will actively recruit students from underrepresented groups to promote diversity, both directly and through the EUReCA! and XSEDE EMPOWER programs. In addition, they will expand the highly successful partnership with Cherry Creek High School to include Cherry Creek Innovation Campus, where high-school teachers will participate in hands-on research through a yearly summer research program. These outreach activities will promote K-12 curriculum innovation and explore students to the excitement of research in STEM (science, technology, engineering and mathematics) fields.The operation mechanism of the NarK transporter has remained elusive for many years. For example, mutagenesis experiments have revealed that the binding-site residues with delocalized pi bonds are essential to the transport activities, but exactly how they influence substrate recruitment and translocation remains unknown. Lin and Guidez will develop novel adaptive-partitioning multi-layer methods that are next-generation ONIOM-like methods with on-the-fly relocated interlayer boundaries. The new algorithms are expected to enable highly accurate and efficient dynamics simulations to unlock the molecular details of anion binding and translocation in NarK. Both the new simulation tools and the mechanistic insights resulting from this project can potentially transform the study of ion migration for many channels and transporters. Through a series of summer outreach programs, this project will provide excellent opportunities to get K-12 teachers and students by exposing them to modern computer modeling techniques, and actively engaging them in biochemical research.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.

通过化学理论，模型和计算方法的资助，科罗拉多大学 - 丹佛大学的Hai Lin和Emilie Gudez将开发和应用新颖的计算算法来研究如何通过膜蛋白nark运输离子。 Nark蛋白将硝酸盐进口（必需元素氮的矿物形式）进入细胞，并从细胞中出口亚硝酸盐（一种可能在高浓度中有毒的代谢产物）。然而，裸蛋白的机制仍然很少理解。非常需要准确有效的计算机建模和模拟，以提供关键的见解。 Lin和Gudez将制定新的多尺度算法，这些算法无缝地结合量子和经典的建模技术，并采用这些算法，他们的研究小组将阐述出关于nark如何帮助牙线如何在细胞膜中传播的原子细节。这项协作研究有可能从根本上提高膜转运蛋白对营养摄取的了解，从而从长远来看，有可能有助于开发与这些蛋白质故障相关的疾病的新型疗法。科罗拉多大学的大学既是西班牙裔服务机构（HSI），也是亚裔美国人美国太平洋岛民服务机构。 Lin和Gudez将积极招募来自代表性不足的团体的学生，以直接和通过Eureca促进多样性！和XSede Empower计划。此外，他们将扩大与Cherry Creek高中的非常成功的合作伙伴关系，包括Cherry Creek Innovation Campus，高中老师将通过年度夏季研究计划参加动手研究。这些外展活动将促进K-12课程创新，并探索学生的STEM研究（科学，技术，工程和数学）领域的兴奋。Nark Transporter的操作机制多年来一直难以捉摸。例如，诱变实验表明，具有离域PI键的结合位点残基对运输活动至关重要，但是它们如何影响底物募集和易位仍然未知。 Lin和Gudez将开发新型的自适应分区多层方法，这些方法是下一代ONIOM样方法，具有在线重新定位的层间边界。预计新算法将使高度准确，有效的动力学模拟能够解锁nark中阴离子结合和易位的分子细节。该项目产生的新仿真工具和机械见解都可以改变许多通道和转运蛋白的离子迁移研究。通过一系列的夏季外展计划，该项目将通过将K-12老师和学生暴露于现代计算机建模技术中，并积极地参与生物化学研究。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子和更广泛的影响来审查Criteria的评估。