DOMAIN-LIGAND BINDING FREE ENERGY CALCULATIONS ON PDC109, A TWO-DOMAIN PROTEIN

双域蛋白 PDC109 的域配体结合自由能计算

• 批准号: 8364321
• 负责人: H-Y KIM
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364321
• 关键词: Affinity; Binding; Binding Sites; Biomedical Research; Cell membrane; Epithelium; Fibronectins; Free Energy; Funding; Grant; Head; High Performance Computing; Individual; Ligand Binding; Ligand Binding Domain; Ligands; Membrane; Membrane Lipids; Methods; National Center for Research Resources; Phospholipids; Phosphorylcholine; Play; Principal Investigator; Proteins; Reporting; Research; Research Infrastructure; Resources; Role; Source; System; Tertiary Protein Structure; United States National Institutes of Health; cost; flexibility; improved; insight; molecular dynamics; sperm cell

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. PDC109 is a 10.6 kDa modular protein containing two fibronectin type II (Fn2) repeats joined by a flexible linker. It plays a major role in bull sperm binding to the oviductal epithelium through its interactions with the sperm cell membrane. These interactions stimulate the efflux of phosphorylcholine (PhC), the soluble head group of the sperm cell membrane lipids, resulting in the specific binding to the PDC109 domains. Long timescale molecular dynamics simulation on PDC109 suggests that PhC binding is correlated with domain-domain interactions. We propose to estimate PhC binding affinity by calculating a potential of mean force (PMF) as a function of distance between binding sites of each domain and the ligand using the adaptive biasing force (ABF) method. The free energy profiles will be calculated on the individual domains and on the intact PDC109. This study will improve interpretation of reported experimental results for the interaction between PDC109 and phospholipid membranes and provide insight into roles of domain-domain interactions on ligand binding in related systems.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 PDC 109是一种10.6 kDa的模块化蛋白，含有两个由柔性接头连接的II型纤连蛋白（Fn 2）重复序列。它通过与精子细胞膜的相互作用在牛精子与输卵管上皮的结合中起主要作用。这些相互作用刺激磷酸胆碱（PhC）的流出，精子细胞膜脂质的可溶性头部基团，导致与PDC 109结构域的特异性结合。长时间尺度的分子动力学模拟PDC 109表明，PhC的结合与结构域之间的相互作用。我们建议通过计算平均力（PMF）的潜力作为每个域和配体的结合位点之间的距离的函数，使用自适应偏置力（ABF）的方法来估计PhC结合亲和力。将在单个结构域和完整的PDC 109上计算自由能曲线。这项研究将改善对PDC 109和磷脂膜之间相互作用的实验结果的解释，并提供相关系统中结构域-结构域相互作用对配体结合的作用的见解。