Interaction of antagonists with calmodulin:: Insights from molecular dynamics simulations
Interaction of antagonists with calmodulin:: Insights from molecular dynamics simulations
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DOI：
10.1021/jm701406e
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发表时间：
2008-06-12
影响因子：
7.3
通讯作者：
Fidy, Judit
中科院分区：
文献类型：
--
作者：
Koevesi, Istvan;Menyhard, Dora K.;Fidy, Judit
我们报告了与三氟拉嗪 (TFP) 和 N-(3,3, 二苯丙基)-N'-[1-R-(3,4-双丁氧基苯基)-乙基]-丙二胺 (DPD) 两个分子结合的钙调蛋白 (CaM) 的 12 ns 全原子分子动力学模拟 (MDS) 和泊松-玻尔兹曼自由能计算 (PBFE) 的结果。 X 射线数据显示这两种复合物的结构非常相似，但拮抗剂的 CaM 结合亲和力显着不同，中性 DPD 更有效。该研究的目的是揭示尽管 TFP 的正电荷有利于结合，但其效力较低的原因。 CHARMM 中的静电能项和 PBFE 方法的结合自由能项表明 TFP 是更好的拮抗剂，而疏水接触的检查支持 DPD 结合。对 PBFE 计算中氨基酸贡献的详细检查表明，空间原因阻碍了 TFP 的有利结合。为成功的药物设计策略给出了结构条件，这也可能受益于电荷-电荷相互作用。
We report results of 12 ns, all-atom molecular dynamics simulation (MDS) and Poisson-Boltzmann free energy calculations (PBFE) on calmodulin (CaM) bound to two molecules of trifluoperazine (TFP) and of N-(3,3, diphenylpropyl)-N'-[1-R-(3,4-bis-butoxyphenyl)-ethyl]-propylenediamine (DPD). X-ray data show very similar structures for the two complexes, yet the antagonists significantly differ with respect to their CaM binding affinities, the neutral DPD is much more potent. The goal of the study was to unravel the reason why TFP is less potent although its positive charge should facilitate binding. The electrostatic energy terms in CHARMM and binding free energy terms of the PBFE approach showed TFP a better antagonist, while inspection of hydrophobic contacts supports DPD binding. Detailed inspection of the amino acid contributions of PBFE calculations unravel that steric reasons oppose the favorable binding of TFP. Structural conditions are given for a successful drug design strategy, which may benefit also from charge-charge interactions.