INVESTIGATION OF MEMBRANE PROPERTIES TO UNDERSTAND PROTEIN FUNCTION MODULATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 对蛋白质-脂质相互作用的定量测量和分子水平的解释对于理解膜-蛋白质的分配、折叠和功能至关重要，膜-蛋白质构成人类基因组的三分之一和所有药物靶标的大多数。我们的目标是使用原子自由能分子动力学模拟来理解控制膜及其相关蛋白质组装的物理规则。我们将计算氨基酸侧链类似物分子和离子的自由能分布，以了解可变形脂质双层的渗透能量，并为生物膜提供新的理论描述。我们还将继续使用多肽作为模型跨膜片段来研究疏水错配的机制，并将开始用极性序列进行模拟，以了解挑战我们疏水匹配概念的新实验数据。此外，我们还将开始探索膜成分对膜变形性和通透性的影响。我们还将探索改进的脂质双层取样方法。这项工作的结果对广泛的生物现象有影响，包括膜蛋白、抗菌肽和病毒肽的活性，以及生物纳米装置。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A quantitative measure and molecular-level interpretation of protein-lipid interactions is essential to understand the partitioning, folding and function of membrane-proteins, which make up a third of the human genome and the majority of all drug targets. We aim to provide an understanding the physical rules that govern the assembly of membranes with their associated proteins using atomistic free energy molecular dynamics simulations. We will calculate free energy profiles of amino acid side chain analog molecules and ions to understand the energetics of permeation through a deformable lipid bilayer and to provide a renewed theoretical description of biological membranes. We will also continue to study the mechanisms of hydrophobic mismatch using polypeptides as model transmembrane segments and will begin simulations with polar sequences to understand new experimental data that challenges our hydrophobic matching concept. In addition, we will begin to explore the role of membrane composition on membrane deformability and permeability. We will also explore improved sampling methods for lipid bilayers. The results of this work have implications for a wide range of biological phenomena, including the activities of membrane proteins, antimicrobial and viral peptides, and bio-nanodevices.