Proteins are dynamic entities that adopt diverse conformations, which play a pivotal role in their function. Understanding these conformations is essential, and protein collective motions, particularly those captured by normal mode (NM) and their linear combinations, provide a robust means for conformational sampling. This work introduces a novel approach to obtaining a uniformly oriented set of a given number of lowest frequency NM combined vectors and generating harmonically equidistant restrained structures along them. They are all thus uniformly located on concentric hyperspheres, systematically covering the defined NM space fully. The generated structures are further relaxed with standard molecular dynamics (MD) simulations to explore the conformational space. The efficiency of the approach we termed "distributed points Molecular Dynamics using Normal Modes" (dpMDNM) was assessed by applying it to hen egg-white lysozyme and human cytochrome P450 3A4 (CYP3A4). To this purpose, we compared our new approach with other methods and analyzed the sampling of existing experimental structures. Our results demonstrate the efficacy of dpMDNM in extensive conformational sampling, particularly as more NMs are considered. Ensembles generated by dpMDNM exhibited a broad coverage of the experimental structures, providing valuable insights into the functional aspects of lysozyme and CYP3A4. Furthermore, dpMDNM also covered lysozyme structures with relatively elevated energies corresponding to transient states not easily obtained by standard MD simulations, in conformity with nuclear magnetic resonance structural indications. This method offers an efficient and rational framework for comprehensive protein conformational sampling, contributing significantly to our understanding of protein dynamics and function.

中文翻译：

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来自多维正则模式超球体上均匀分布点的大分子构象的扩展采样。


蛋白质是采用多种构象的动态实体，这些构象在其功能中起着关键作用。了解这些构象是必不可少的，蛋白质集体运动，特别是那些被正常模式 （NM） 捕获的运动及其线性组合，为构象采样提供了一种强大的手段。这项工作引入了一种新方法，可以获得给定数量的最低频率 NM 组合向量的均匀定向集，并沿它们生成谐波等距约束结构。因此，它们都均匀地位于同心超球体上，系统地完全覆盖了定义的 NM 空间。通过标准分子动力学 （MD） 模拟进一步放松生成的结构，以探索构象空间。我们称之为“使用正态模式的分布点分子动力学”（dpMDNM） 的方法的效率是通过将其应用于鸡蛋清溶菌酶和人细胞色素 P450 3A4 （CYP3A4） 来评估的。为此，我们将我们的新方法与其他方法进行了比较，并分析了现有实验结构的采样。我们的结果证明了 dpMDNM 在广泛的构象采样中的功效，特别是当考虑更多的 NM 时。dpMDNM 生成的集合展示了实验结构的广泛覆盖范围，为溶菌酶和 CYP3A4 的功能方面提供了有价值的见解。此外，dpMDNM 还覆盖了溶菌酶结构，其能量相对升高，对应于标准 MD 模拟不容易获得的瞬态，符合核磁共振结构指示。 该方法为全面的蛋白质构象采样提供了一个高效合理的框架，为我们理解蛋白质动力学和功能做出了重大贡献。