Mahdizadeh Sayyed Jalil, Carlesso Antonio, Eriksson Leif A
Department of Chemistry and Molecular Biology, University of Gothenburg 405 30 Göteborg Sweden
RSC Adv. 2020 May 26;10(33):19720-19729. doi: 10.1039/d0ra01895c. eCollection 2020 May 20.
The selectivity of the ligand MKC9989, as inhibitor of the Inositol-Requiring Enzyme 1α (IRE1α) transmembrane kinase/ribonuclease protein, towards the residue K907 in the context of Schiff base formation, has been investigated by employing an array of techniques including Multi-Conformation Continuum Electrostatics (MCCE) simulations, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations, covalent docking, and Molecular Dynamics (MD) simulations. According to the MCCE results, K907 displays the lowest p value among all 23 lysine residues in IRE1α. The MMCE simulations also indicate a critical interaction between K907 and D885 within the hydrophobic pocket which increases significantly at low protein dielectric constants. The QM/MM calculations reveal a spontaneous proton transfer from K907 to D885, consistent with the low p value of K907. A Potential Energy Surface (PES) scan confirms the lack of energy barrier and transition state associated with this proton transfer reaction. Covalent docking and MD simulations verify that the protein pocket containing K907 can effectively stabilize the inhibitor by strong π-π and hydrogen bonding interactions. In addition, Radial Distribution Function (RDF) analysis shows that the imine group formed in the chemical reaction between MKC9989 and K907 is inaccessible to water molecules and thus the probability of imine hydrolysis is almost zero. The results of the current study explain the high selectivity of the MKC9989 inhibitor towards the K907 residue of IRE1α.
通过采用包括多构象连续静电学（MCCE）模拟、量子力学/分子力学（QM/MM）计算、共价对接和分子动力学（MD）模拟在内的一系列技术，研究了配体MKC9989作为肌醇需求酶1α（IRE1α）跨膜激酶/核糖核酸酶蛋白抑制剂，在席夫碱形成背景下对残基K907的选择性。根据MCCE结果，K907在IRE1α的所有23个赖氨酸残基中显示出最低的p值。MMCE模拟还表明，K907与疏水口袋内的D885之间存在关键相互作用，在低蛋白介电常数下这种相互作用会显著增加。QM/MM计算揭示了从K907到D885的自发质子转移，这与K907的低p值一致。势能面（PES）扫描证实了与该质子转移反应相关的能量屏障和过渡态的缺失。共价对接和MD模拟验证了含有K907的蛋白口袋可以通过强烈的π-π和氢键相互作用有效地稳定抑制剂。此外，径向分布函数（RDF）分析表明MKC9989与K907之间化学反应形成的亚胺基团对水分子不可及，因此亚胺水解的概率几乎为零。当前研究结果解释了MKC9989抑制剂对IRE1α的K907残基具有高选择性的原因。
