Computational and Structural Biotechnology Journal ( IF 6 ) Pub Date : 2020-06-25 , DOI: 10.1016/j.csbj.2020.06.034 Shusuke Suzuki 1 , Toshiya Nakamura 1 , Ryosuke Saito 1 , Yuta Terauchi 1 , Kentaro Kawai 2 , Midori Takimoto-Kamimura 3 , Noriyuki Kurita 1
To elucidate structural changes in the retinoic acid receptor-related orphan receptor gamma (RORγt) induced by the binding of an agonist or an inverse agonist, we conducted molecular dynamics (MD) simulations in explicit water. In addition, ab initio fragment molecular orbital calculations were carried out for certain characteristic structures obtained from the MD simulations to reveal important interactions between the amino acid residues of RORγt, and to distinguish the different effects in the binding of an agonist and an inverse agonist on the structure of RORγt. The results elucidate that the hydrogen bond between His479 of helix11 (H11) and Tyr502 of helix12 (H12) is important to keep the H12 conformation in the agonist-bound RORγt. In contrast, in the inverse-agonist-bound RORγt, the side chain of His479 rotates, significantly weakening the interaction between His479 and Tyr502, leading to a conformational change in H12. Therefore, the present molecular simulations clearly indicate that the conformational change in the side chain of His479 in the inverse-agonist-bound RORγt is the main reason for the H12 destabilization induced by the binding of the inverse agonist. Such a conformational change does not occur on the binding of the agonist in RORγt, owing to the strong hydrogen bond between His479 and Tyr502.
中文翻译:
反向激动剂结合引起的视黄酸受体相关孤儿受体的结构变化:分子动力学和从头算分子轨道模拟。
为了阐明由激动剂或反向激动剂的结合引起的视黄酸受体相关的孤儿受体γ(RORγt)的结构变化,我们在显性水中进行了分子动力学(MD)模拟。另外,从头开始对通过MD模拟获得的某些特征结构进行了片段分子轨道计算,以揭示RORγt氨基酸残基之间的重要相互作用,并区分激动剂和反向激动剂对RORγt结构的不同影响。结果表明,helix11(H11)的His479和helix12(H12)的Tyr502之间的氢键对于将H12构象保留在激动剂结合的RORγt中很重要。相反,在反向激动剂结合的RORγt中,His479的侧链旋转,显着削弱了His479和Tyr502之间的相互作用,导致H12的构象变化。因此,目前的分子模拟清楚地表明,与反向激动剂结合的RORγt中His479侧链的构象变化是反向激动剂结合导致H12不稳定的主要原因。由于His479和Tyr502之间的强氢键,这种构象变化不会在RORγt中的激动剂结合时发生。