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Accurate docking is achieved by decoupling systematic sampling from scoring.

机译：通过将系统采样与评分脱钩，可以实现准确的对接。

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摘要

This dissertation discusses two main projects from my thesis work. The first project focuses on the development of a small molecule docking program, SKATE, for drug discovery. The second project focuses on the critical analysis of the thermal stability of a mini-protein, FSD-1.;SKATE is a novel approach to small molecule docking. It removes any inter-dependence between sampling and scoring to improve docking accuracy. SKATE systematically and exhaustively samples a ligand's conformational, rotational and translational degrees of freedom, as constrained by a receptor pocket, to find sterically allowed poses. A total of 266 ligands were re-docked to their respective receptors to assess SKATE's performance. The results show that SKATE was able to sample poses within 2 A RMSD of the native structure for 97% of the cases. The best performing scoring function was able to rank a pose that is within 2 A RMSD of the native structure as the top-scoring pose for 83% of the cases. Compared to published data, SKATE has a higher self-docking accuracy rate than or is at least comparable to GOLD, Glide, MolDock and Surflex. The cross-docking accuracy of SKATE was assessed by docking 83 ligands to their respective receptors. The cross-docking results were comparable to those in published methods.;Mini-proteins that contain fewer than 50 amino acids often serve as model systems for studying protein folding because their small size makes long time-scale simulations possible. However, not all mini-proteins are created equal. The stability and structure of FSD-1, a 28-residue mini-protein that adopts the betabetaalpha zinc-finger motif independent of zinc binding, was investigated using circular dichroism (CD), differential scanning calorimetry (DSC), and replica-exchange molecular dynamics (REMD). FSD-1's broad melting transition, similar to that of a helix-to-coil transition, was observed in CD, DSC, and REMD experiments. The N-terminal beta-hairpin was found to be flexible. FSD-1's apparent melting temperature of 41°C may be a reflection of the melting of its alpha-helical segment instead of the entire protein. Thus, FSD-1's status as a model system for studying protein folding should be reconsidered despite its attractiveness for being small in size and it was designed to contain essential helix, sheet, and turn secondary structures.;An electronic copy of this dissertation is available online at www.ccb.wustl.edu/ ∼jafeng
机译：本文讨论了论文工作中的两个主要项目。第一个项目侧重于开发用于药物发现的小分子对接程序SKATE。第二个项目侧重于对小蛋白FSD-1的热稳定性进行严格分析； SKATE是一种新的小分子对接方法。它消除了采样和评分之间的任何相互依存关系，从而提高了对接精度。 SKATE系统地，详尽地取样受受体口袋限制的配体的构象，旋转和翻译自由度，以找到空间允许的姿势。总共266个配体重新对接至各自的受体，以评估SKATE的性能。结果表明，在97％的情况下，SKATE能够在原始结构的2 A RMSD范围内采样姿势。表现最佳的评分功能是将83％的案例中的最高评分姿势排在本机结构的2 A RMSD之内。与已发布的数据相比，SKATE具有比GOLD，Glide，MolDock和Surflex更高的自对接准确率，或者至少与之相当。通过将83个配体对接至它们各自的受体来评估SKATE的交叉对接准确性。交叉对接的结果与已发表的方法相当。包含少于50个氨基酸的微型蛋白质通常用作研究蛋白质折叠的模型系统，因为它们的小尺寸使长时间的模拟成为可能。但是，并非所有的微蛋白都是一样的。使用圆二色性（CD），差示扫描量热法（DSC）和复制交换分子研究了FSD-1的稳定性和结构，FSD-1是一种具有28个残基的小蛋白，具有独立于锌结合的beta-betaalpha锌指基序。动态（REMD）。在CD，DSC和REMD实验中观察到了FSD-1的宽解链转变，类似于螺旋-螺旋转变。发现N末端β-发夹是柔性的。 FSD-1的表观解链温度为41°C，可能反映了其α-螺旋片段而非整个蛋白质的解链。因此，尽管FSD-1的体积小且具有吸引力，但它被设计为包含必需的螺旋，片状和转二级结构，因此应重新考虑其作为研究蛋白质折叠的模型系统的地位。在线www.ccb.wustl.edu/~jafeng

著录项

  • 作者

    Feng, Jianwen A.;

  • 作者单位

    Washington University in St. Louis.;

  • 授予单位 Washington University in St. Louis.;
  • 学科 Chemistry Biochemistry.;Chemistry Pharmaceutical.;Biology Bioinformatics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 138 p.
  • 总页数 138
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;药物化学;
  • 关键词

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