Immune checkpoint blockade of signaling pathways such as PD‐1/PD‐L1 has recently opened up a new avenue for highly efficient immunotherapeutic strategies to treat cancer. Since tumor microenvironments are characterized by lower pH (5.5‐7.0), pH‐dependent protein‐ligand interactions can be exploited as efficient means to regulate drug affinity and specificity for a variety of malignancies. In this article, we investigate the mechanism and kinetics of pH‐dependent binding and unbinding processes for the PD‐1/PD‐L1 checkpoint pair employing classical molecular dynamics simulations. Two representative pH levels corresponding to circumneutral physiological conditions of blood (pH 7.4) and acidic tumor microenvironment (pH 5.5) are considered. Our calculations demonstrate that pH plays a key role in protein‐ligand interactions with small pH changes leading to several orders of magnitude increase in binding affinity. By identifying the binding pocket in the PD‐1/PD‐L1 complex, we show a pivotal role of the His68 protonation state of PD‐1in the complex stabilization at low pH. The results on the reaction rate constants are in qualitative agreement with available experimental data. The obtained molecular details are important for further engineering of binding/unbinding kinetics to formulate more efficient immune checkpoint blockade strategies.

中文翻译：

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从分子动力学来看，PD-1和PD-L1免疫检查点蛋白之间的pH依赖性相互作用动力学。

诸如PD-1 / PD-L1等信号通路的免疫检查点封锁最近为高效的癌症免疫治疗策略开辟了一条新途径。由于肿瘤微环境的特征是较低的pH（5.5-7.0），因此可以利用pH依赖的蛋白质-配体相互作用作为调节各种恶性肿瘤药物亲和力和特异性的有效手段。在本文中，我们使用经典的分子动力学模拟研究了PD-1 / PD-L1检查点对的pH依赖性结合和解结合过程的机理和动力学。考虑了两个代表性的pH值，分别对应于血液的周围生理条件（pH 7.4）和酸性肿瘤微环境（pH 5.5）。我们的计算表明，pH在蛋白质-配体相互作用中起着关键作用，pH值的变化很小，导致结合亲和力增加了几个数量级。通过鉴定PD-1 / PD-L1复合物中的结合口袋，我们显示了PD-1的His68质子化状态在低pH下复合物稳定中的关键作用。反应速率常数的结果与可用的实验数据在质量上一致。所获得的分子细节对于进一步设计结合/未结合动力学以制定更有效的免疫检查点封锁策略非常重要。反应速率常数的结果与可用的实验数据在质量上一致。所获得的分子细节对于进一步设计结合/未结合动力学以制定更有效的免疫检查点封锁策略非常重要。反应速率常数的结果与可用的实验数据在质量上一致。获得的分子详细信息对于进一步设计结合/解离动力学以制定更有效的免疫检查点封锁策略非常重要。