COMPUTER SIMULATION STUDIES OF HIV 1 SPECIFIC VPU PROTEIN

计算机模拟分子动力学（MD）计算是 旨在补充旨在阐明结构的实验 病毒蛋白U（Vpu）的特征，一种81个残基的蛋白质， 完全由人类免疫缺陷病毒1型，HIV-1编码。 Vpu有两种不同的生物活性， 分离的结构域：诱导CD 4降解 内质网（ER）中的受体和病毒增强 颗粒从质膜释放。 前一个功能 涉及Vpu的胞质（CYTO）序列，后者涉及 跨膜（TM）结构域。 该项目的目标是利用 新的恒定压力和温度MD方法，以详细说明 HIV-1特异性Vpu如何以及在何处与细胞相互作用 件. 我们已经发表了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）， 膜系统 我们最近还进行了一次模拟 一种跨膜合成离子通道的研究 21个残基肽螺旋束。 我们建议在这些基础上， MD模拟结果，并探讨了疏水性的相互作用 Vpu TM结构域肽（Vpu 1-27）与模型膜。 下一个是 鉴于它们作为单价体生物通道的潜力 阳离子，我们建议确定的低聚物的行为， 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的溶液结构 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， 水性和混合的亲水和疏水溶剂。 最后如果 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，这将进行 在宾夕法尼亚大学和其他地方，在HIV-1特异性Vpu上。

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.