A new approach to solvent determination in QM/MM-based X-ray crystallographic refinement

基于 QM/MM 的 X 射线晶体学精修中溶剂测定的新方法

• 批准号: 8834159
• 负责人: Lance M Westerhoff
• 金额: $ 14.11万
• 依托单位: QUANTUMBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834159
• 关键词: Active Sites; Address; Affinity; Agreement; Algorithms; Benchmarking; Binding; Chemicals; Collaborations; Communities; Complex; Computer software; Coupled; Crystallography; Data; Databases; Docking; Drug Design; Drug Industry; Drug Interactions; Experimental Models; Failure; Grant; Hand; Health; Human; Hydration status; Hydrogen Bonding; Industry; Industry Collaborators; Laboratories; Lead; Letters; Ligands; Literature; Macromolecular Complexes; Manuals; Maps; Measures; Mediating; Metals; Methodology; Methods; Michigan; Modeling; Muramidase; Nuclear Magnetic Resonance; Phase; Play; Population; Positioning Attribute; Probability; Proteins; Protocols documentation; Publishing; Quantum Mechanics; R-factor; Reporting; Research; Resolution; Resources; Roentgen Rays; Role; Running; Scientist; Services; Site; Small Business Innovation Research Grant; Solvents; Structure; System; Techniques; Time; Universities; Validation; Water; Weight; Work; X-Ray Crystallography; base; cofactor; density; drug discovery; electron density; human disease; improved; innovation; insight; novel strategies; novel therapeutics; protein complex; protein structure; public health relevance; quantum; receptor; research study; resistance factors; restraint; statistics; success; three dimensional structure

DESCRIPTION (provided by applicant): Success in structure based drug design (SBDD) and fragment based drug design are ultimately largely dependent upon the quality of the three-dimensional (3D) structure of protein:ligand and protein:protein complexes that is the core structural technique. Both nuclear magnetic resonance (NMR) and X-ray crystallography are used to determine experimental models pertaining to these structures. Through a previous project, QuantumBio Inc. improved the quality of the X-ray refinement through integration of the Company's quantum mechanics (QM) based DivCon Discovery Suite with the PHENIX crystallographic package. This natural synergy brings the power and accuracy of quantum mechanics to the field of X-ray refinement as it plays to the core strengths of QM methods (e.g. no atom types, support for more "exotic" chemical systems, metals, and so on). This early success has led to an expanded commercial offering that was released in February 2014. The present proposal is focused on a further improvement the accuracy of the X-ray refinement protocol by incorporating improved explicit solvent structure determination. It is quite clear - an there is a growing body of evidence that indicates - that the influences of solvent have significant impact on the ligand and receptor structure as well as on the energetics of the binding. Very often exploration of an active site - such as in lead discovery and optimization - is a question of whether or not additional "unseen" waters are mediating the interactions between ligand, protein, cofactor, and so on. An intrinsic problem in macromolecular X-ray crystallography is that only a partial number of solvent molecules can be unambiguously revealed due to the resolution limitations. Unlike approaches such as WaterMap, conventional 3D-RISM, and SZMAP, which are used to predict waters regardless of their agreement with experiment, the key innovation of this method is through the use of an advanced explicit water determination algorithm to filter crystallographic data and generate the complete, experimental solvent structure within the macromolecular complex. In preliminary studies performed with our partners, the evidence that this approach is applicable to the problem at hand is quite compelling. Specifically, the results for the 2.5 A lysozyme crystal structure 2EPE have shown that the application of the new solvation methodology leads to twice as many waters or a 100% improvement in the hydration shell for the low-resolution lysozyme structure accompanied by the improvement of the overall crystallographic statistics. The method also successfully found key, crystallographic "bridging" waters along with active site pocket stabilization waters when executed on the protein:ligand complex represented in PDBid:3ERQ. Together, these preliminary results are quite encouraging, and completion of this SBIR will allow us to completely generalize and validate the method and prepare it for commercial deployment.

描述（由申请人提供）：基于结构的药物设计（SBDD）和基于片段的药物设计的成功最终在很大程度上取决于作为核心结构技术的蛋白质：配体和蛋白质：蛋白质复合物的三维（3D）结构的质量。核磁共振 (NMR) 和 X 射线晶体学都用于确定与这些结构相关的实验模型。通过之前的项目，QuantumBio Inc. 通过将公司基于量子力学 (QM) 的 DivCon Discovery Suite 与 PHENIX 晶体包集成，提高了 X 射线精化的质量。这种自然的协同作用将量子力学的力量和准确性带入 X 射线精化领域，因为它发挥了 QM 方法的核心优势（例如，无原子类型、支持更多“奇异”化学系统、金属等）。这一早期成功导致了 2014 年 2 月发布的扩大的商业产品。当前提案的重点是通过纳入改进的显式溶剂结构测定来进一步提高 X 射线精修方案的准确性。很明显 - 并且有越来越多的证据表明 - 溶剂的影响对配体和受体结构以及结合的能量有显着影响。通常，对活性位点的探索——例如先导化合物的发现和优化——是 额外的“看不见的”水是否介导配体、蛋白质、辅因子等之间的相互作用的问题。大分子 X 射线晶体学的一个固有问题是，由于分辨率的限制，只能明确显示部分溶剂分子。与 WaterMap、传统 3D-RISM 和 SZMAP 等用于预测水而不管其与实验是否相符的方法不同，该方法的关键创新在于使用先进的显式水测定算法来过滤晶体学数据并在大分子复合物内生成完整的实验性溶剂结构。在与我们的合作伙伴进行的初步研究中，该方法适用于当前问题的证据非常令人信服。具体而言，2.5 A 溶菌酶晶体结构 2EPE 的结果表明，应用新的溶剂化方法可以使低分辨率溶菌酶结构的水合壳增加两倍或 100% 改善，同时整体晶体学统计数据也得到改善。当对 PDBid:3ERQ 中表示的蛋白质：配体复合物执行该方法时，该方法还成功找到了关键的晶体“桥接”水以及活性位点袋稳定水。总之，这些初步结果非常令人鼓舞，完成 SBIR 将使我们能够完全推广和验证该方法，并为商业部署做好准备。