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体的形成是大多数生物过程的基础。自动对接是一种重要的工具，用于获得这些相互作用的机制理解，并支持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设计的生物医学应用。众所周知，大分子中从氨基侧链重排到柔性环和结构域运动的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的最严重限制之一。我们已经开发了一种分层的数据结构，称为“柔性树”（FT），允许有效的表示和编码的构象子空间的大分子，我们已经证明使用FT对接灵活的配体分子到灵活的受体。我们建议将FT纳入广泛使用的对接程序AutoDock，以支持对接柔性配体对柔性受体。具体而言，我们将：1）使用新的基于FT的对接引擎扩展AutoDock对接软件套件：AutoDock-FR，它将支持多分辨率接收器灵活性，以及可插入的搜索引擎和评分功能。我们还将扩展图形用户界面AutoDockTools，以支持这种新的对接后端; 2）扩展FT，使其能够更好地表示柔性环和双聚体侧链，并连接蛋白质柔性预测方法，以支持用户构建FT; 3）创建分子复合物的数据集，其中大分子柔性已知是自动对接程序成功所需的。该数据集将用于测试和验证拟议的软件，并将提供给社区，为评估对接方法提供基准。这个开放源码软件开发项目将以软件工程的最佳做法为基础，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取代和组合。我们提出的模块化设计还定义了一个清晰和干净的机制，用于在新算法可用时添加新算法，使AutoDock-FR可进化和可维护。这项工作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。我们提出的完全成熟、用户友好、高度可定制、完全文档化的软件将在一个已经广泛使用的流行对接程序中提供，这将有助于其传播和采用。AutoDock-FR将大大扩展自动对接将成功使用的生物学问题的范围。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社区，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.