Development and assessment of methods for membrane protein structure prediction

膜蛋白结构预测方法的开发和评估

• 批准号: 10708625
• 负责人: Lucy Forrest
• 金额: $ 79.39万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708625
• 关键词: Acute; Address; Amino Acid Sequence; Anti-Bacterial Agents; Behavior; Bioinformatics; Biophysics; Cell membrane; Code; Collaborations; Complement; Computer software; Computing Methodologies; Data; Deuterium; Development; Electron Spin Resonance Spectroscopy; Elements; Event; FDA approved; Genes; Genome; Homologous Gene; Human; Hydrogen; Hydrophobicity; Intuition; Journals; Maryland; Membrane; Membrane Proteins; Methodology; Methods; Modeling; Molecular; Molecular Computations; Molecular Conformation; National Heart, Lung, and Blood Institute; Nature; Nucleic Acids; Online Systems; Organism; Pharmaceutical Preparations; Positioning Attribute; Process; Proteins; Resolution; Sampling; Science; Sequence Alignment; Structural Models; Structure; Technology; Therapeutic Studies; Translating; Water; base; biophysical techniques; database structure; fascinate; improved; insight; interest; machine learning method; molecular dynamics; movie; nervous system disorder; online resource; protein function; protein structure; protein structure prediction; public database; tool

The ability to reliably align the amino acid sequences of proteins is a key requirement for confirming evolutionary relationships, identifying conserved elements, and enabling homology-based structural modeling. However, the more dissimilar the sequences, the more challenging it is to compute their alignments accurately, and the challenge is particularly acute for membrane proteins due to their largely greasy composition. This year, we continued to develop our software for alignment of membrane protein sequences. In collaboration with Dr. Staritzbichler (U. Leipzig), we added several new structurally-oriented features to our online server for AlignMe, available at http://www.bioinfo.mpg.de/AlignMe (Staritzbichler R, Yaklich E, Sarti E, Ristic N, Hildebrand PW, Forrest LR, 2022, Nucleic Acids Res 50:W29). Protein function has traditionally been interpreted largely in the context of "snapshots" of structural data that reflect single frames in a movie of molecular behavior. To facilitate incorporation of biophysical data into representations of proteins, we have developed an approach together with the Faraldo-Gomez lab (NHLBI) to combine rates of exchange between hydrogen and deuterium (HDX) with molecular dynamics simulations. We developed a comprehensive tutorial for this method (Lee SP, Bradshaw RT, Marinelli F, Kihn KC, Smith AK, Wintrode PL, Deredge DJ, Faraldo-Gomez JD, Forrest LR, 2022, Living Journal of Computational Molecular Science 3:1521) and illustrated the application of the method to the problem of rare-event sampling in an antibacterial target called PhuS (Kihn KC, Wilson T, Smith AK, Bradshaw RT, Wintrode PL, Forrest LR, Wilks A, Deredge DJ, 2021, Biophys J 120:5141) in collaboration with the Deredge and Wintrode labs (U. Maryland).

可靠地比对蛋白质氨基酸序列的能力是确认进化关系、识别保守元件和实现基于同源性的结构建模的关键要求。然而，序列越不相似，准确计算它们的比对就越具有挑战性，并且对于膜蛋白来说，由于其大部分油脂成分，这一挑战尤其严峻。今年，我们继续开发用于膜蛋白序列比对的软件。我们与 Staritzbichler 博士（莱比锡大学）合作，在 AlignMe 在线服务器中添加了一些新的面向结构的功能，可访问 http://www.bioinfo.mpg.de/AlignMe（Staritzbichler R、Yaklich E、Sarti E、Ristic N、Hildebrand PW、Forrest LR、2022、Nucleic Acids） 第 50 号决议：W29）。 传统上，蛋白质功能主要是在结构数据“快照”的背景下解释的，这些数据反映了分子行为电影中的单个帧。为了促进将生物物理数据纳入蛋白质的表示中，我们与 Faraldo-Gomez 实验室 (NHLBI) 合作开发了一种方法，将氢和氘 (HDX) 之间的交换率与分子动力学模拟结合起来。我们为此方法开发了一个综合教程（Lee SP、Bradshaw RT、Marinelli F、Kihn KC、Smith AK、Wintrode PL、Deredge DJ、Faraldo-Gomez JD、Forrest LR，2022，Living Journal of Computational Molecular Science 3:1521），并说明了该方法在名为 PhuS (Kihn) 的抗菌目标中的罕见事件采样问题上的应用 KC、Wilson T、Smith AK、Bradshaw RT、Wintrode PL、Forrest LR、Wilks A、Deredge DJ，2021，Biophys J 120:5141）与 Deredge 和 Wintrode 实验室（美国马里兰州）合作。