AutoDock-FR: A Modular Approach to Flexible Receptor Docking

描述（由申请人提供）：分子相互作用和分子组装的形成是大多数生物过程的基础。自动对接是获得这些相互作用机制理解和支持生物医学应用的重要工具，从药物设计到用于研究化学途径和确定癌症和代谢紊乱等疾病的治疗靶点的化学探针的设计。众所周知，从氨基侧链重排到大分子中的柔性环和结构域运动等各种构象变化通常是与配体相互作用机制的重要组成部分。在对接模拟过程中将大分子表示为刚性分子是这些技术最严重的局限性之一。我们开发了一种称为“灵活性树”（FT）的分层数据结构，允许大分子的构象子空间的有效表示和编码，并且我们已经演示了使用FT将柔性配体分子对接到柔性受体上。我们建议在广泛使用的对接程序AutoDock中加入FT，以支持柔性配体与柔性受体的对接。具体来说，我们将：1)用一个新的基于ft的对接引擎扩展AutoDock对接软件套件：AutoDock- fr，它将支持多分辨率受体的灵活性，以及可插拔的搜索引擎和评分功能。我们还将扩展图形用户界面AutoDockTools来支持这个新的对接后端；2)扩展FT，使其具有更好地表示柔性环和旋转侧链的能力，以及界面蛋白质柔韧性预测方法，以支持用户构建FT；3)创建一个分子复合物的数据集，其中大分子的灵活性是自动对接过程成功所必需的。该数据集将用于测试和验证拟议的软件，并将提供给社区，并为评估对接方法提供基准。这个开源软件开发项目将基于软件工程的最佳实践，并产生一个模块化的、基于组件的软件环境，在这个环境中，搜索技术和评分功能可以被替换和组合。我们提出的模块化设计还定义了一个清晰的机制，以便在新算法可用时添加新算法，使AutoDock-FR具有可扩展性和可维护性。这一努力将极大地利用社区开发的方法，并提供前所未有的互操作性。我们提出的成熟的、用户友好的、高度可定制的、有完整文档的软件将在一个已经被广泛使用的、受欢迎的对接项目中提供，这将有助于它的传播和采用。AutoDock-FR将极大地扩展自动对接将成功用于的生物问题的范围。它将影响许多化学家和生物学家的研究，将计算工具的使用扩展到更广泛的科学家群体，并极大地影响生物医学研究。

DESCRIPTION (provided by applicant): Molecular interactions and the formation of molecular assemblies are underpinning most biological processes. Automated docking is an important tool for gaining a mechanistic understanding of these interactions and supporting biomedical applications ranging from drug design to the design of chemical probes used to investigate chemical pathways and identify therapeutic targets for diseases such as cancer and metabolic disorders. It is known that a variety of conformational changes ranging from amino side chain rearrangement to flexible loops and domain motions in macromolecules are often an essential and integral part of the interaction mechanism with a ligand. The representation of macromolecules as rigid molecules during the docking simulation is one of the most severe limitations of these techniques. We have developed a hierarchical data structure called the "Flexibility Tree" (FT) allowing the efficient representation and encoding of conformational subspaces of macromolecules and we have demonstrated using FTs for docking flexible ligand molecules into flexible receptors. We propose to incorporate the FT in the widely used docking program AutoDock in order to support docking flexible ligands against flexible receptors. Specifically, we will: 1) extend the AutoDock docking software suite with a new FT-based docking engine: AutoDock-FR that will support multi-resolution receptor flexibility, and pluggable search engines and scoring functions. We will also extend the Graphical User Interface AutoDockTools to support this new docking backend; 2) extend the FT with the ability to better represent flexible loops and rotatmeric side chains, and interface protein flexibility prediction methods to support users in building FTs; and 3) create a dataset of molecular complexes in which macromolecular flexibility is known to be required for the success of automated docking procedures. This dataset will be used to test and validate the proposed software and will be made available to the community and provide a benchmark for evaluating docking methods. This Open-Source software development project will be based on best practices in software engineering and result in a modular, component-based software environment in which search techniques and scoring functions can be substituted and combined. The modular design we propose also defines a clear and clean mechanism for the addition of new algorithms as they become available, making AutoDock-FR evolvable and maintainable. This effort will greatly leverage methods developed by the community and provide unprecedented inter- operability. The fully fledged, user friendly, highly customizable, fully documented software we propose will be made available within an already widely used a popular docking program which will help its dissemination and adoption. AutoDock-FR will greatly extend the range of biological problems for which automated docking will be used successfully. It will impact the research of many chemists and biologist, extend the use of computational tools to a wider community of scientists, and greatly impact biomedical research. PUBLIC HEALTH RELEVANCE: Automated docking has proven to be a useful tool for a variety of applications including: rational drug design, lead optimization and the design of chemical probes, however, the rigid models of macromolecules used by most docking programs severely limits the success rate of automated docking. We propose to extend the widely used and well established docking program AutoDock with a new docking engine AutoDock-FR that will allow for the representation of flexible receptor and the optimization of the receptor's conformation in the presence of the ligand during the docking simulation. This new capability in AutoDock will impact the research of many computational and medicinal chemists and biologist and contribute to our understanding of biological processes and thus significantly impact research in biomedicine.