Chen Rong, Chung Shin-Ho
Research School of Biology , Australian National University , Acton , ACT 2601 , Australia.
Biochemistry. 2018 May 8;57(18):2704-2710. doi: 10.1021/acs.biochem.8b00268. Epub 2018 Apr 25.
Molecular dynamics simulations are employed to determine the inhibitory mechanisms of three drugs, 5-(4-phenoxybutoxy)psoralen (PAP-1), vernakalant, and flecainide, on the voltage-gated K channel Kv1.5, a target for the treatment of cardiac arrhythmia. At neutral pH, PAP-1 is neutral, whereas the other two molecules carry one positive charge. We show that PAP-1 forms stable dimers in water, primarily through hydrophobic interactions between aromatic rings. All three molecules bind to the cavity between the Ile508 and Val512 residues from the four subunits of the channel. Once bound, the drug molecules are flexible, with the average root-mean-square fluctuation being between 2 and 3 Å, which is larger than the radius of gyration of a bulky amino acid. The presence of a monomeric PAP-1 causes the permeating K ion to dehydrate, thereby creating a significant energy barrier. In contrast, vernakalant blocks the ion permeation primarily via an electrostatic mechanism and, therefore, must be in the protonated and charged form to be effective.
分子动力学模拟被用于确定三种药物，即5-(4-苯氧基丁氧基)补骨脂素（PAP-1）、维纳卡兰和氟卡尼，对电压门控钾通道Kv1.5的抑制机制，该通道是治疗心律失常的一个靶点。在中性pH值下，PAP-1呈中性，而其他两种分子带有一个正电荷。我们发现PAP-1在水中形成稳定的二聚体，主要是通过芳环之间的疏水相互作用。所有这三种分子都与通道四个亚基中Ile508和Val512残基之间的腔结合。一旦结合，药物分子具有柔性，平均均方根波动在2至3 Å之间，这大于一个庞大氨基酸的回转半径。单体PAP-1的存在会使渗透的钾离子脱水，从而产生显著的能量屏障。相比之下，维纳卡兰主要通过静电机制阻断离子渗透，因此，必须处于质子化和带电形式才有效。
