• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Mechanism of NAD(P)H:quinone reductase: Ab initio studies of reduced flavin and combine ab initio and molecular mechanics analysis of the hydride transfer.
【24h】

Mechanism of NAD(P)H:quinone reductase: Ab initio studies of reduced flavin and combine ab initio and molecular mechanics analysis of the hydride transfer.

机译：NAD（P）H：醌还原酶的机制：从头算研究黄素还原，并结合从头算和分子力学分析氢化物转移。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Quinone reductase (QR1) is a flavin-adenine-dinucleotide (FAD)-containing homodimer that carries out a nicotinamide-adenine-dinucleotide-(phosphate) (NAD(P)H)-dependent, obligatory two-electron reduction of quinones. NAD(P)H and the FAD isoalloxazine ring are parallel-stacked, such that nicotinamide-C4 (C4N) and flavin N5 (N5F) are 4 Å apart, ideally positioned for hydride transfer. The proposed QR1 mechanism involves a charge transfer relay using two flavin-adjacent amino acids. We studied quantum chemically at the ab-initio RHF/STO-3G, RHF/6-31G(d) and density functional theory (DFT) B3LYP/6-31G(d) levels several x-ray structure configurations of the ring: oxidized, reduced and reduced after charge relay.; Atomic charges, three-dimensional electrostatic potentials, Highest Occupied (HOMO's) and Lowest Unoccupied (LUMO's) Molecular Orbitals were calculated. Several partially overlapping LUMO's form a path for the reducing electrons from N5F to N1F and O2F. Protonation of O2F neutralizes the ring electronegativity. There is a LUMO at His161, a residue proposed to act in the charge relay. A proton from Tyr155 is transferred to O2F, and another may be transferred from His161 to Tyr155, resulting in equalization of the ring negative charge. The reduced isoalloxazine ring is maintained planar by the protein, providing an additional reaction driving force.; Hydride transfer from NADH to FAD was analyzed using ab initio calculations, semiempirical optimizations, and molecular dynamics. The transition state was approximated by semiempirical optimization moving only the hydride. A three dimensional grid of ab initio DFT B3LYP/6-31G(d) single point energy calculations was performed around the paths to the transition state. A reaction coordinate surface with a saddle point was obtained and relaxed by optimization of the cofactors. Due to molecular strains, the energy of the transition state is too high (about 80 kcal/mol). The charge relay lowers this energy slightly, but trial amino acid side chains relaxation calculations indicate that the protein must relax to lower it further.; Quantum mechanical results were used to run CHARMM molecular dynamics relaxing the whole protein before the reaction and at the transition state. Molecular dynamics relaxation using the quantum mechanically-derived charges lowers the reaction barrier by 70 kcal/mol. Distances between important residues show that the relaxation facilitates the charge relay by diminishing the path for proton transfer.
机译：醌还原酶（QR1）是一种含黄素腺嘌呤二核苷酸（FAD）的同型二聚体，可进行烟酰胺-腺嘌呤二核苷酸-（磷酸酯）（NAD（P）H）依赖性的必不可少的二电子还原醌。 NAD（P）H和FAD异恶嗪环平行堆叠，因此烟酰胺-C4（C4N）和黄素N5（N5F）相距4Å，非常适合氢化物转移。拟议的QR1机制涉及使用两个黄素相邻氨基酸的电荷转移中继。我们在 ab-initio RHF / STO-3G，RHF / 6-31G（d）和密度泛函理论（DFT）B3LYP / 6-31G（d）的水平上对量子化学进行了研究环的结构配置：电荷中继后被氧化，还原和还原。计算了原子电荷，三维静电势，最高占有（HOMO）和最低未占有（LUMO）分子轨道。几个部分重叠的LUMO形成了一条将电子从N5F还原到N1F和O2F的路径。 O2F的质子化可中和环的电负性。 His161上有一个LUMO，这是一个拟在电荷继电器中起作用的残基。质子从Tyr155转移到O2F，另一个质子从His161转移到Tyr155，导致环负电荷均等。还原的异四嗪环被蛋白质保持为平面，从而提供了额外的反应驱动力。使用 ab initio 计算，半经验优化和分子动力学分析了从NADH到FAD的氢化物转移。通过仅移动氢化物的半经验优化来近似过渡态。在到过渡态的路径周围执行了从头算 DFT B3LYP / 6-31G（d）单点能量计算的三维网格。通过优化辅因子，获得并缓和了具有鞍点的反应坐标表面。由于分子应变，过渡态的能量太高（约80 kcal / mol）。电荷继电器会稍微降低这种能量，但是试验性氨基酸侧链松弛计算表明蛋白质必须松弛才能进一步降低它。量子力学结果用于运行CHARMM分子动力学，从而使整个蛋白质在反应前和过渡态处松弛。使用量子机械衍生的电荷进行的分子动力学弛豫将反应势垒降低了70 kcal / mol。重要残基之间的距离表明，弛豫通过减少质子转移路径来促进电荷中继。

著录项

  • 作者

    Cavelier, German.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biophysics General.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 210 p.
  • 总页数 210
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物物理学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号