Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
Snapshot of the equilibrium dynamics of a drug bound to HIV-1 reverse transcriptase.
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抗艾滋病药物利匹韦林经历构象变化以结合 HIV-1 逆转录酶并保留对抗耐药突变的效力。据报道，我们发现水分子在药物结合中发挥着重要作用。飞秒实验和理论揭示了利匹韦林与 HIV-1 逆转录酶结合的分子水平动力学。两个腈取代基（-CN）在药物的每个臂上各有一个，其振动光谱与其在晶体和溶液中相似的蛋白质环境一致。二维振动回波光谱揭示了一种腈的干燥环境，而另一种腈则出人意料地与移动的水分子形成氢键，这在早期的 X 射线结构中并未发现。超快丁腈-水动力学通过模拟得到证实。分辨率更高（1.51 Å）的 X 射线结构确实揭示了水-药物相互作用网络。尽管结合袋扩大且结构发生变化，但维持关键的锚定氢键可能有助于保留利匹韦林对抗袋突变的效力。
The anti-AIDS drug rilpivirine undergoes conformational changes to bind HIV-1 reverse transcriptase and retain potency against drug-resistance mutations. Our discovery that water molecules play an essential role in the drug binding is reported. Femtosecond experiments and theory expose molecular level dynamics of rilpivirine bound to HIV-1 reverse transcriptase. The two nitrile substituents (-CN), one on each arm of the drug, have vibrational spectra consistent with their protein environments being similar in crystals and in solutions. Two-dimensional vibrational-echo spectroscopy reveals a dry environment for one nitrile while unexpectedly the other is hydrogen-bonded to a mobile water molecule, not identified in earlier X-ray structures. Ultrafast nitrile-water dynamics are confirmed by simulations. A higher (1.51 Å) resolution X-ray structure indeed reveals a water-drug interaction network. Maintenance of a crucial anchoring hydrogen bond, despite the enlargement and structural variation of the binding pocket, may help retain the potency of rilpivirine against the pocket mutations.