Institute for Drug Discovery, Leipzig University, Leipzig, Saxony 04103, Germany.
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37235, USA.
Structure. 2022 Aug 4;30(8):1157-1168.e3. doi: 10.1016/j.str.2022.04.013. Epub 2022 May 20.
Conformational changes are an essential component of functional cycles of many proteins, but their characterization often requires an integrative structural biology approach. Here, we introduce and benchmark ConfChangeMover (CCM), a new method built into the widely used macromolecular modeling suite Rosetta that is tailored to model conformational changes in proteins using sparse experimental data. CCM can rotate and translate secondary structural elements and modify their backbone dihedral angles in regions of interest. We benchmarked CCM on soluble and membrane proteins with simulated Cα-Cα distance restraints and sparse experimental double electron-electron resonance (DEER) restraints, respectively. In both benchmarks, CCM outperformed state-of-the-art Rosetta methods, showing that it can model a diverse array of conformational changes. In addition, the Rosetta framework allows a wide variety of experimental data to be integrated with CCM, thus extending its capability beyond DEER restraints. This method will contribute to the biophysical characterization of protein dynamics.
构象变化是许多蛋白质功能循环的重要组成部分，但它们的特征通常需要综合结构生物学方法。在这里，我们引入并基准测试了 ConfChangeMover（CCM），这是一种新的方法，内置在广泛使用的大分子建模套件 Rosetta 中，旨在使用稀疏的实验数据来模拟蛋白质的构象变化。CCM 可以旋转和移动二级结构元素，并修改它们在感兴趣区域的主链二面角。我们分别使用模拟的 Cα-Cα 距离约束和稀疏的实验双电子-电子共振（DEER）约束对可溶性和膜蛋白进行了 CCM 基准测试。在这两个基准测试中，CCM 都优于最先进的 Rosetta 方法，表明它可以模拟各种构象变化。此外，Rosetta 框架允许将各种实验数据与 CCM 集成，从而超越 DEER 约束扩展其功能。这种方法将有助于蛋白质动力学的生物物理特征描述。
