Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation

叠加独立 X 射线数据分析，增强肟 OP-ChE 重新激活 项目摘要。大量平民和军人容易受到 有机磷（OP）暴露至今仍然是一个不幸的危险。两者，神经毒剂OP 有机磷农药是现实且令人震惊的重大危害。最近恐怖的巨大神经 叙利亚发生的药剂中毒事件以及全球每天与有机磷农药相关的死亡事件 暴露揭示了目前采用的应对OP措施普遍缺乏适当性 中毒。重点是可负担性、可用性和功效。超过 200 个 AChE 和 过去 25 年沉积在 PDB 中的 BChE 结构揭示了异常一致的蛋白质构象， 不仅是蛋白质主链，而且是大多数氨基酸侧链。这种明显的缺失 在低温和固态晶体状态下记录的构象灵活性，表现为 与极高的催化输出形成对比，特别是在又长又窄的 AChE 活性中心 峡谷。 AChE 和 BChE 蛋白的催化必需、热驱动、“呼吸”波动 骨干网长期以来一直被怀疑和提出，但从未得到明确证明 实验性地。特别是对于肟再活化反应，主链波动似乎至关重要，因为 在狭窄的活动中心空间中，对共价连接的OP的访问受到高度限制，进一步受到影响 共价结合的 OP 缀合物。对于加速、高效的再激活分子的设计来说，至关重要的是 了解活性中心的哪些部分具有移动和促进亲核肟的结构倾向 以几何最佳方式接近磷原子。该信息被记录在 数百个已解析和沉积的 ChE 结构，我们的目标是将其提取为有用的形式。 我们期望检测到幅度虽小但本质上是系统性的结构波动。我们最初的 手动分析证实了这些预期。

Overlay independent X-ray data analysis for enhanced oxime OP-ChE reactivation Project Summary. Vulnerability of large civilian and military populations to organophosphate (OP) exposure remains an unfortunate peril of the present day. Both, nerve agent OPs and OP based pesticides are realistic and alarmingly significant hazards. Recent horrifying massive nerve agent poisoning episodes in Syria and daily worldwide fatalities associated with OP based pesticide exposures reveal general lack of appropriateness of currently employed measures for counteracting OP intoxications. The emphasis is on affordability, availability and efficacy. More than two hundred AChE and BChE structures deposited in PDB in the past 25 years reveal unusually consistent protein conformations, not only of protein backbones but also of majority of amino acid side chains. This apparent absence of conformational flexibility registered at the low temperature and in the solid crystaline state, appears as a contrast to an extreemely high catalytic output, in particular in the long and narrow AChE active center gorge. Catalytically essential, thermally driven, „breathing“ fluctuations of the AChE and BChE protein backbones have long been suspected and proposed but have never been clearly demonstrated experimentally. In particular for oxime reactivation reactions backbone fluctuations appear essential due to highly restricted access to covalently attached OPs in the narrow actice center space impacted further by covalently bound OP conjugates. For design of an accelerated, efficient reactivator molecule it is critical to know what parts of active center have structural predisposition to move and facilitate nucleophilic oxime approach to the phosphorus atom in geometrically optimal fashion. This information is encripted in hundreds of resolved and deposited ChE structures and our goal is to extract it to an useful form. We expect to detect structural fluctuations small in magnitude yet systematic in nature. Our initial manual analyses confirm those expectations.