Steinbuch Centre for Computing, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
Department of Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
PLoS One. 2020 Nov 16;15(11):e0242072. doi: 10.1371/journal.pone.0242072. eCollection 2020.
Proteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein's structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore how in silico protein structure determination based on replica-exchange molecular dynamics (REMD) can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain an ensemble with native-like conformations of high quality. We find that contact-guided REMD is capable of delivering physically reasonable models of a protein's structure.
蛋白质是复杂的生物分子，在生物体中执行关键任务。了解蛋白质的结构对于详细了解其生理功能至关重要。尽管实验技术取得了令人难以置信的进展，但蛋白质结构的确定仍然昂贵、耗时且艰巨。这就是为什么经常使用计算机模拟来补充或解释实验数据。在这里，我们探讨了基于 replica-exchange 分子动力学（REMD）的计算蛋白质结构确定如何受益于包含源自理论和实验来源的接触信息，例如直接耦合分析或 NMR 光谱。为了反映错误和嘈杂数据的影响，我们探究了错误的接触如何影响模拟的集合。具体来说，我们整合了不同数量的随机选择的天然和非天然接触，并探索这种偏差如何引导模拟向天然状态发展。我们研究了实现丰富类似天然构象所需的接触数量，并展示了这种方法的能力和局限性。在模拟中坚持大约 75%的真实阳性接触的阈值，我们获得了具有高质量类似天然构象的集合。我们发现，接触引导的 REMD 能够提供蛋白质结构的物理合理模型。
