Department of Chemistry and Biophysics Program, University of Michigan, 930 North University Avenue, Chem 2006, Ann Arbor, MI 48109, USA.
Structure. 2012 Sep 5;20(9):1453-62. doi: 10.1016/j.str.2012.08.007.
For a variety of problems in structural biology, low-resolution maps generated by electron microscopy imaging are often interpreted with the help of various flexible-fitting computational algorithms. In this work, we systematically analyze the quality of final models of various proteins obtained via molecular dynamics flexible fitting (MDFF) by varying the map-resolution, strength of structural restraints, and the steering forces. We find that MDFF can be extended to understand conformational changes in lower-resolution maps if larger structural restraints and lower steering forces are used to prevent overfitting. We further show that the capabilities of MDFF can be extended by combining it with an enhanced conformational sampling method, temperature-accelerated molecular dynamics (TAMD). Specifically, either TAMD can be used to generate better starting configurations for MDFF fitting or TAMD-assisted MDFF (TAMDFF) can be performed to accelerate conformational search in atomistic simulations.
对于结构生物学中的各种问题，通常借助各种灵活拟合的计算算法来解释由电子显微镜成像生成的低分辨率图谱。在这项工作中，我们通过改变图谱分辨率、结构约束强度和导向力，系统地分析了通过分子动力学灵活拟合 (MDFF) 获得的各种蛋白质最终模型的质量。我们发现，如果使用更大的结构约束和更低的导向力来防止过度拟合，MDFF 可以扩展到理解低分辨率图谱中的构象变化。我们进一步表明，通过将其与增强的构象采样方法（温度加速分子动力学 (TAMD)）相结合，可以扩展 MDFF 的功能。具体来说，TAMD 可以用于为 MDFF 拟合生成更好的起始构象，或者可以执行 TAMD 辅助的 MDFF（TAMDFF）以加速原子模拟中的构象搜索。
