Free energy along drug-protein binding pathways interactively sampled in virtual reality.
Free energy along drug-protein binding pathways interactively sampled in virtual reality.
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DOI：
10.1038/s41598-023-43523-x
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发表时间：
2023-10-04
影响因子：
4.6
通讯作者：
Glowacki, David R.
中科院分区：
文献类型：
--
作者：
Deeks, Helen M.;Zinovjev, Kirill;Barnoud, Jonathan;Mulholland, Adrian J.;van der Kamp, Marc W.;Glowacki, David R.
我们描述了一个两步的方法，结合在虚拟现实（iMD-VR）中的交互式分子动力学与自由能（FE）的计算，探索在分子水平上的生物过程的动力学。我们将这种组合方法称为iMD-VR-FE。第一阶段涉及使用最先进的“人在环”iMD-VR框架来生成各种蛋白质-配体解结合途径，受益于人类空间和化学直觉的复杂性。第二阶段涉及使用iMD-VR采样的路径作为初始猜测，用于定义基于路径的反应坐标，我们可以使用FE方法从该坐标获得相应的自由能分布。为了研究该方法的性能，我们应用iMD-VR-FE来研究苯甲脒配体与胰蛋白酶蛋白的解结合。使用iMD-VR-FE计算的结合自由能对于每个途径是相似的，表明内部一致性。此外，所得的自由能分布可以区分对应于各种蛋白质-配体构象的途径之间的能量差异（例如，帮助识别更有利的途径）并能够识别沿着途径的亚稳态（沿着）。两步iMD-VR-FE方法为研究人员提供了一种直观的方法来测试生物分子系统中候选途径的假设，快速获得定性和定量的见解。
We describe a two-step approach for combining interactive molecular dynamics in virtual reality (iMD-VR) with free energy (FE) calculation to explore the dynamics of biological processes at the molecular level. We refer to this combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art ‘human-in-the-loop’ iMD-VR framework to generate a diverse range of protein–ligand unbinding pathways, benefitting from the sophistication of human spatial and chemical intuition. Stage two involves using the iMD-VR-sampled pathways as initial guesses for defining a path-based reaction coordinate from which we can obtain a corresponding free energy profile using FE methods. To investigate the performance of the method, we apply iMD-VR-FE to investigate the unbinding of a benzamidine ligand from a trypsin protein. The binding free energy calculated using iMD-VR-FE is similar for each pathway, indicating internal consistency. Moreover, the resulting free energy profiles can distinguish energetic differences between pathways corresponding to various protein–ligand conformations (e.g., helping to identify pathways that are more favourable) and enable identification of metastable states along the pathways. The two-step iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses for candidate pathways in biomolecular systems, quickly obtaining both qualitative and quantitative insight.
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影响因子：
5.7
作者：
Capelli, Riccardo;Carloni, Paolo;Parrinello, Michele
通讯作者：
Parrinello, Michele
影响因子：
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Tautz, F. Stefan
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作者：
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通讯作者：
Brooks, Charles L., III
影响因子：
4.4
作者：
Amabilino, Silvia;Bratholm, Lars A.;Glowacki, David R.
通讯作者：
Glowacki, David R.