大肠杆菌 DHFR 中的动态局部相互作用可控制酶抑制的动力学屏障,Journal of Chemical Information and Modeling

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大肠杆菌 DHFR 中的动态局部相互作用可控制酶抑制的动力学屏障
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-07-25 , DOI: 10.1021/acs.jcim.3c00818
Ebru Cetin ₁ , Tandac F Guclu ₁ , Isik Kantarcioglu _{1,

2} , Ilona K Gaszek ₂ , Erdal Toprak ₂ , Ali Rana Atilgan ₁ , Burcu Dedeoglu ₃ , Canan Atilgan ₁

Affiliation

二氢叶酸还原酶 (DHFR) 是一个重要的药物靶点，也是一种用于了解酶动力学的经过深入研究的模型蛋白。DHFR 在叶酸合成中的关键作用使其成为了解蛋白质功能和蛋白质进化机制的理想候选者。在这项研究中，为了了解新提出的 DHFR 抑制剂 4'-脱氧甲基甲氧苄啶 (4'-DTMP) 如何改变进化轨迹，我们研究了导致其性能优于甲氧苄啶 (TMP) 的相互作用。为了阐明 4'-DTMP 的抑制机制，我们首先通过计算和实验证实，TMP 和 4'-DTMP 突变的相对结合自由能成本是相同的，指出特征差异的根源是动力学而非热力学。然后，我们采用基于相互作用的分析，首先关注活性位点，然后关注整个酶。我们证实 4'-DTMP 中的极性修饰会诱导与酶的额外局部相互作用，特别是 M20 环。随着氢键网络的变化，这些变化会传播到整个酶。为了阐明变构相互作用，我们通过基于网络的群落分析来支持我们的分析，并表明成功的抑制剂必须避免抑制剂结合的 DHFR 环域的分割。

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Kinetic Barrier to Enzyme Inhibition Is Manipulated by Dynamical Local Interactions in E. coli DHFR

Dihydrofolate reductase (DHFR) is an important drug target and a highly studied model protein for understanding enzyme dynamics. DHFR’s crucial role in folate synthesis renders it an ideal candidate to understand protein function and protein evolution mechanisms. In this study, to understand how a newly proposed DHFR inhibitor, 4′-deoxy methyl trimethoprim (4′-DTMP), alters evolutionary trajectories, we studied interactions that lead to its superior performance over that of trimethoprim (TMP). To elucidate the inhibition mechanism of 4′-DTMP, we first confirmed, both computationally and experimentally, that the relative binding free energy cost for the mutation of TMP and 4′-DTMP is the same, pointing the origin of the characteristic differences to be kinetic rather than thermodynamic. We then employed an interaction-based analysis by focusing first on the active site and then on the whole enzyme. We confirmed that the polar modification in 4′-DTMP induces additional local interactions with the enzyme, particularly, the M20 loop. These changes are propagated to the whole enzyme as shifts in the hydrogen bond networks. To shed light on the allosteric interactions, we support our analysis with network-based community analysis and show that segmentation of the loop domain of inhibitor-bound DHFR must be avoided by a successful inhibitor.

更新日期：2023-07-25

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