Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.
Electrostatic channeling in P. falciparum DHFR-TS: Brownian dynamics and Smoluchowski modeling.
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DOI：
10.1016/j.bpj.2014.09.039
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发表时间：
2014-11
影响因子：
3.4
通讯作者：
Vincent T. Metzger;Changsun Eun;Peter M. Kekenes-Huskey;G. Huber;J. A. McCammon
中科院分区：
文献类型：
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作者：
Vincent T. Metzger;Changsun Eun;Peter M. Kekenes-Huskey;G. Huber;J. A. McCammon
我们对双功能恶性疟原虫二氢叶酸还原酶-胸苷合成酶(恶性疟原虫DHFR-TS)进行了布朗动力学模拟和Smoluchowski连续体模拟，目的是了解TS活性部位产生的二氢叶酸静电通道到DHFR活性部位。布朗动力学模拟和Smoluchowski连续介质模拟的结果表明，与主要利什曼原虫DHFR-TS相比，恶性疟原虫DHFR-TS在生理pH(7.0m)和离子强度(150m M)下具有较低但显著的静电介导的通道效率(∼15-25%)。我们还发现，去除位于DHFR和TS活性中心之间的关键碱性残基的电荷显著降低了OFP的通道效率。虽然已知几种原生动物DHFR-TS酶具有相似的三级和四级结构，但结构、活性部位几何形状和电荷分布的细微差异似乎既影响静电介导的底物沟道，也影响基于邻近的底物沟道。
We perform Brownian dynamics simulations and Smoluchowski continuum modeling of the bifunctionalPlasmodium falciparumdihydrofolate reductase-thymidylate synthase (P. falciparumDHFR-TS) with the objective of understanding the electrostatic channeling of dihydrofolate generated at the TS active site to the DHFR active site. The results of Brownian dynamics simulations and Smoluchowski continuum modeling suggest that compared toLeishmania majorDHFR-TS,P. falciparumDHFR-TS has a lower but significant electrostatic-mediated channeling efficiency (∼15–25%) at physiological pH (7.0) and ionic strength (150 mM). We also find that removing the electric charges from key basic residues located between the DHFR and TS active sites significantly reduces the channeling efficiency ofP. falciparumDHFR-TS. Although several protozoan DHFR-TS enzymes are known to have similar tertiary and quaternary structure, subtle differences in structure, active-site geometry, and charge distribution appear to influence both electrostatic-mediated and proximity-based substrate channeling.