<br>氧气环境中一氧化碳与血红蛋白的结合：分子动力学的力场发展,Journal of Chemical Theory and Computation

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氧气环境中一氧化碳与血红蛋白的结合：分子动力学的力场发展
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2024-02-24 , DOI: 10.1021/acs.jctc.4c00029
Mingrui Jiang, Chi-Hua Yu, Zhiping Xu, Zhao Qin

一氧化碳 (CO) 是碳基燃料（例如木材、煤炭、汽油或天然气）不完全燃烧的副产品。由于火灾事故或发动机中的不完全燃烧，大量产生的CO会导致严重的生命威胁，因为CO会与结合血红蛋白的氧气(O ₂ )竞争，使人缺氧。虽然对于CO中毒患者有高压O ₂疗法，但富O ₂环境中CO解离的纳米级机制尚不完全清楚。在本研究中，我们构建了与CHARMM兼容的经典力场参数来模拟血红蛋白、CO和O ₂之间的配位相互作用，并利用力场揭示了O ₂对血红蛋白和CO之间结合强度的影响。密度泛函理论和 Car-Parrinello 分子动力学模拟用于获得键能和平衡几何形状，并且我们使用通过前馈神经网络模型启用的机器学习来获得经典力场参数。我们使用力场引导分子动力学模拟来表征不同模拟富O ₂环境下血红蛋白-CO 键断裂前的机械强度。结果表明，当O ₂以小于∼2.8 Å的距离接近血红素的Fe ²⁺时，CO和Fe ²⁺之间的配位键在断裂过程中观察到的峰值力降低至50% 。我们的元动力学模拟测量的自由能景观也显示了这种减弱效应。我们的工作表明，血红蛋白-CO键周围富含O ₂的环境有效地削弱了这种键合，因此设计O ₂递送载体至该位点有助于减轻CO结合，这可能为CO的从头药物设计提供启示。中毒。

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Binding of Carbon Monoxide to Hemoglobin in an Oxygen Environment: Force Field Development for Molecular Dynamics

Carbon monoxide (CO) is a byproduct of the incomplete combustion of carbon-based fuels, such as wood, coal, gasoline, or natural gas. As incomplete combustion in a fire accident or in an engine, massively produced CO leads to a serious life threat because CO competes with oxygen (O₂) binding to hemoglobin and makes people suffer from hypoxia. Although there is hyperbaric O₂ therapy for patients with CO poisoning, the nanoscale mechanism of CO dissociation in the O₂-rich environment is not completely understood. In this study, we construct the classical force field parameters compatible with the CHARMM for simulating the coordination interactions between hemoglobin, CO, and O₂, and use the force field to reveal the impact of O₂ on the binding strength between hemoglobin and CO. Density functional theory and Car–Parrinello molecular dynamics simulations are used to obtain the bond energy and equilibrium geometry, and we used machine learning enabled via a feedforward neural network model to obtain the classical force field parameters. We used steered molecular dynamics simulations with a force field to characterize the mechanical strength of the hemoglobin–CO bond before rupture under different simulated O₂-rich environments. The results show that as O₂ approaches the Fe²⁺ of heme at a distance smaller than ∼2.8 Å, the coordination bond between CO and Fe²⁺ is reduced to 50% bond strength in terms of the peak force observed in the rupture process. This weakening effect is also shown by the free energy landscape measured by our metadynamics simulation. Our work suggests that the O₂-rich environment around the hemoglobin–CO bond effectively weakens the bonding, so that designing of O₂ delivery vector to the site is helpful for alleviating CO binding, which may shed light on de novo drug design for CO poisoning.

更新日期：2024-02-24

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