Exploring Product Release from Yeast Cytosine Deaminase with Metadynamics
Exploring Product Release from Yeast Cytosine Deaminase with Metadynamics
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DOI：
10.1021/acs.jpcb.3c07972
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发表时间：
2024-03-22
影响因子：
3.3
通讯作者：
McCarty，James
中科院分区：
文献类型：
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作者：
Croney，Kayla A.;McCarty，James
酵母胞嘧啶脱氨酶（yCD）酶/5-氟胞嘧啶前药系统是靶向化疗药物的有希望的候选者。在前药转化为毒性化疗药物5-氟尿嘧啶（5-FU）后，从酶缓慢释放产物限制了酶/前药系统的总体催化效率。在这里，我们提出了一个计算研究的产品释放的抗癌药物，5-FU，从yCD使用代谢。我们提出了一个比较5-FU药物的天然酶产品，尿嘧啶。我们使用体积为基础的metadaptics计算产品释放的自由能景观，并显示出适度的结合亲和力的产品的酶，与实验一致。接下来，我们使用罕见的metadaptics估计从Kramers时间依赖性速率理论的无偏释放速率，并找到一个有利的比较，以实验的产品释放速度较慢的5-FU系统。我们的工作展示了如何使用自适应采样方法来研究工程酶/前药系统的蛋白质-配体解结合过程，并深入了解yCD/5-FU系统产物释放的分子机制。
The yeast cytosine deaminase (yCD) enzyme/5-fluorocytosine prodrug system is a promising candidate for targeted chemotherapeutics. After conversion of the prodrug into the toxic chemotherapeutic drug, 5-fluorouracil (5-FU), the slow product release from the enzyme limits the overall catalytic efficiency of the enzyme/prodrug system. Here, we present a computational study of the product release of the anticancer drug, 5-FU, from yCD using metadynamics. We present a comparison of the 5-FU drug to the natural enzyme product, uracil. We use volume-based metadynamics to compute the free energy landscape for product release and show a modest binding affinity for the product to the enzyme, consistent with experiments. Next, we use infrequent metadynamics to estimate the unbiased release rate from Kramers time-dependent rate theory and find a favorable comparison to experiment with a slower rate of product release for the 5-FU system. Our work demonstrates how adaptive sampling methods can be used to study the protein–ligand unbinding process for engineering enzyme/prodrug systems and gives insights into the molecular mechanism of product release for the yCD/5-FU system.