Development and assessment of methods for membrane protein structure prediction

可靠地比对蛋白质氨基酸序列的能力是确认进化关系、鉴定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，精确计算它们的比对就越具有挑战性，并且由于膜蛋白的组成很大程度上是油腻的，因此对于膜蛋白的挑战尤其严重。今年，我们继续开发用于膜蛋白序列比对的软件。与Staritzbichler博士合作（U。Leipzig），我们为AlignMe的在线服务器添加了几个新的面向结构的功能，可在http://www.bioinfo.mpg.de/AlignMe上获得（Staritzbichler R，Yaklich E，Sarti E，Ristic N，Hildebrand PW，Forrest LR，2022，Nucleic Acids Res 50：W29）。 传统上，蛋白质功能的解释主要是在结构数据的“快照”的背景下进行的，这些结构数据反映了分子行为电影中的单个帧。为了便于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）一起开发了一种方法，将氢和氘（HDX）之间的交换率与分子动力学模拟联合收割机结合起来。我们为这种方法开发了一个全面的教程（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），并与Deredge和Wintrode labs（U.马里兰州）。

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).