Biophysical Effects of Reversible Lipid Modification of Integral Membrane Proteins

完整膜蛋白可逆脂质修饰的生物物理效应

• 批准号: 2221796
• 负责人: Shikha Nangia
• 金额: $ 41.53万
• 依托单位: Syracuse University
• 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: 2022-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2221796&HistoricalAwards=false
• 关键词: Biophysical; Effects; Reversible; Lipid; Modification

There is growing evidence that integral membrane proteins, which represent approximately 30% of the proteins in the human body, undergo lipid modifications to maintain their healthy biological function. However, how lipidation regulates the function of the membrane proteins is not well understood. This project will uncover the effect of lipid modification on these integral membrane proteins. Using computer modeling and simulations, the project will study the changes in protein structure due to the attachment of the lipid. The project will also examine the interaction of the protein with other integral membrane proteins and the change in their biological activity in the presence and absence of the attached lipid. The project involves concepts from many disciplines, including chemistry, biology, physics, mathematics, and computer science, and provides an excellent opportunity to train students with different academic backgrounds. The project will provide scientific training to undergraduate students through a cohort-based approach that will engage a team of 5–10 undergraduates in a ten-week summer research project. The project will focus on recruiting and better preparing underrepresented minority students for graduate school. Students will be equipped with research experiences, fundamental knowledge, and professional skills to successfully transition to doctoral programs in STEM disciplines.This research project is motivated by a lack of knowledge pertaining to the molecular biophysics of the interplay of lipids and proteins—the structural and functional workhorses of life. The focus will be on palmitoylation, the covalent attachment of palmitic acid to a protein's cysteine residue via a thioester bond. The addition of palmitoyl chain(s) regulates a protein's dynamics and biological function by altering specific protein-protein and protein-lipid interactions. The project will (i) characterize the impact of palmitoylation on protein's structure using all-atom simulations to investigate the structural and chemical asymmetry introduced in proteins by the addition of palmitoyl chains; (ii) compute the influence of palmitoylation on protein-lipid dynamics via multiscale simulations to elucidate palmitoylated protein dynamics over tens of microseconds, and tens of nanometers in biomimetic cellular and subcellular membrane environments; and (iii) evaluate the consequence of palmitoylation on protein function via the application of the newly developed and validated protein association energy landscape (PANEL) method to capture protein assembly. Results obtained will be verified by data-sharing collaborations with experimental research groups. The use of an extensive computational toolkit and bioinformatics approaches with in vitro experiments will establish the fundamental structural-functional and dynamical aspects of palmitoylated membrane proteins in their lipid landscapes.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.

越来越多的证据表明，约占人体蛋白质 30% 的完整膜蛋白会进行脂质修饰以维持其健康的生物学功能。然而，脂质化如何调节膜蛋白的功能尚不清楚。该项目将利用计算机建模和模拟揭示脂质修饰对这些整合膜蛋白的影响，研究由于脂质附着而导致的蛋白质结构的变化。该项目还将研究蛋白质与其他整合膜的相互作用。蛋白质及其生物活性的变化该项目涉及化学、生物学、物理、数学和计算机科学等多个学科的概念，为培养不同学术背景的学生提供了绝佳的机会。该项目将为本科生提供科学训练。该项目将采用基于队列的方法，让 5-10 名本科生参与为期十周的夏季研究项目，重点是招募和更好地为研究生院的学生提供研究经验和基础知识。 ，以及成功过渡到博士的专业技能STEM 学科的项目。该研究项目的动机是缺乏有关脂质和蛋白质（生命的结构和功能主力）相互作用的分子生物物理学的知识。该研究项目的重点是棕榈酰化，即棕榈酸与蛋白质的共价连接。通过硫酯键添加蛋白质的半胱氨酸残基，通过改变特定的蛋白质-蛋白质和蛋白质-脂质相互作用来调节蛋白质的动力学和生物功能。 (i) 使用全原子模拟来表征棕榈酰化对蛋白质结构的影响，以研究通过添加棕榈酰链而在蛋白质中引入的结构和化学不对称性；(ii) 通过多尺度模拟计算棕榈酰化对蛋白质-脂质动力学的影响阐明仿生细胞和亚细胞膜环境中数十微秒和数十纳米的棕榈酰化蛋白质动力学；以及 (iii) 通过以下方式评估棕榈酰化对蛋白质功能的影响；应用新开发和验证的蛋白质关联能量景观（PANEL）方法来捕获蛋白质组装，所获得的结果将通过与实验研究小组的数据共享合作进行验证，并在体外实验中使用广泛的计算工具包和生物信息学方法。将建立棕榈酰化膜蛋白在其脂质景观中的基本结构功能和动力学方面。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。