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，占人体蛋白质约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，脂化如何调节膜蛋白的功能还不清楚。该项目将揭示脂质修饰对这些整合膜蛋白的影响。利用计算机建模和模拟，该项目将研究由于脂质的附着而引起的蛋白质结构的变化。该项目还将研究蛋白质与其他膜蛋白的相互作用，以及在存在和不存在附着脂质的情况下其生物活性的变化。该项目涉及许多学科的概念，包括化学，生物学，物理学，数学和计算机科学，并为培养具有不同学术背景的学生提供了绝佳的机会。该项目将通过基于队列的方法为本科生提供科学培训，该方法将在为期十周的夏季研究项目中吸引5-10名本科生的团队。该项目将侧重于招收人数不足的少数民族学生，并为他们进入研究生院做好更好的准备。学生将具备研究经验，基础知识和专业技能，以成功过渡到STEM学科的博士课程。本研究项目的动机是缺乏有关脂质和蛋白质相互作用的分子生物物理学知识-生命的结构和功能的主力。重点将放在棕榈酰化，棕榈酸的共价连接蛋白质的半胱氨酸残基通过硫酯键。棕榈酰链的添加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学功能。该项目将（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，以阐明数十微秒内的棕榈酰化蛋白质动力学，和几十纳米的仿生细胞和亚细胞膜环境;和（iii）通过应用新开发和验证的蛋白质缔合能量景观（PANEL）方法来捕获蛋白质组装，评估棕榈酰化对蛋白质功能的影响。将通过与实验研究小组的数据共享合作来验证所获得的结果。使用广泛的计算工具包和生物信息学方法与体外实验将建立棕榈酰化膜蛋白在其脂质landscapes.This奖项反映了NSF的法定使命的基本结构功能和动力学方面的支持，并已被认为是值得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。