COMPUTER SIMULATION STUDIES OF HIV 1 SPECIFIC VPU PROTEIN

HIV 1特异性VPU蛋白的计算机模拟研究

• 批准号: 6564591
• 负责人: MICHAEL L. KLEIN
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564591
• 关键词: computer simulation; human immunodeficiency virus 1; membrane proteins; protein structure function; structural biology; virus infection mechanism; virus protein

Computer simulation molecular dynamics (MD) calculations are proposed to complement experiments designed to elucidate structural characteristics of virus protein U (Vpu), an 81-residue protein which is encoded exclusively by human immunodeficiency virus type 1, HIV-1. Vpu has two distinct biological activities that are controlled by separate structural domains: Induction of the degradation of the CD4 receptor in the endoplasmic reticulum (ER) and augmentation of virus particle release from the plasma membrane. The former function involves the cytoplasmic (CYTO) sequences of Vpu and the latter the transmembrane (TM) domain. The goal of this project is to utilize new constant pressure and temperature MD methodologies to detail how, and where, HIV-1-specific Vpu interacts with cellular components. We have already published MD simulation results for the biologically relevant bilayer phase of the phospholipid dipalmitoylphosphatidylcholine (DPPC), which a well-recognized model membrane system. We have also recently carried out a simulation study of a membrane-spanning synthetic ion channel formed by a four- helix bundle of 21-residue peptides. We propose to build on these MD simulation results and explore the interactions of the hydrophobic Vpu TM domain peptide (Vpu 1-27) with a model membrane. Next, in light of their potential to act as biological channel for monvalent cations, we propose to determine the behavior of oligomers of the wild-type peptide Vpu 1-27 in a lipid bilayer. The MD technique will also be used to investigate the solution structure of the Vpu CYTO domain (peptide Vpu 32-81) to compare with contemporary experiments. To do so, we will carry out extensive MD simulation is aqueous and mixed hydrophilic and hydrophobic solvents. Finally, if the afore mentioned studies are successful, we will then attempt to characterize the behavior of HIV-1-specific Vpu in other membrane- mimetic environments including, bilayers, micelles and Langmuir monolayers. These computer simulation studies are designed to complement NMR and diffraction experiments, which will be carried out at UPENN and elsewhere, on HIV-1-specific Vpu.

计算机模拟分子动力学（MD）计算是 提议补充旨在阐明结构的实验 病毒蛋白 U (Vpu) 的特征，这是一种 81 个残基的蛋白， 由 1 型人类免疫缺陷病毒 HIV-1 专门编码。 Vpu 有两种不同的生物活性，受控于 单独的结构域：CD4 降解的诱导 内质网（ER）受体和病毒增强 粒子从质膜释放。 前一个函数 涉及 Vpu 的细胞质 (CYTO) 序列，后者是 跨膜 (TM) 结构域。 该项目的目标是利用 新的恒压和温度 MD 方法详述 HIV-1 特异性 Vpu 如何以及在何处与细胞相互作用 成分。 我们已经发布了 MD 模拟结果 磷脂的生物学相关双层相 二棕榈酰磷脂酰胆碱（DPPC），这是一个公认的模型 膜系统。 我们最近也进行了模拟 由四离子形成的跨膜合成离子通道的研究 21 个残基肽的螺旋束。 我们建议在此基础上 MD模拟结果并探讨疏水性的相互作用 Vpu TM 结构域肽 (Vpu 1-27) 与模型膜。 下一个， 鉴于它们作为单价生物通道的潜力 阳离子，我们建议确定低聚物的行为 脂质双层中的野生型肽 Vpu 1-27。 MD技术将 也可用于研究 Vpu CYTO 的解决方案结构 域（肽 Vpu 32-81）与当代比较 实验。 为此，我们将进行广泛的 MD 模拟 水性溶剂和混合的亲水性和疏水性溶剂。 最后，如果 上述研究取得成功，我们将尝试 表征 HIV-1 特异性 Vpu 在其他膜中的行为 模拟环境，包括双层、胶束和 Langmuir 单层。 这些计算机模拟研究旨在 补充核磁共振和衍射实验，将进行 在 UPENN 和其他地方，研究 HIV-1 特异性 Vpu。