ADFR: A Modular Software Framework for Docking into Flexible Receptors

项目摘要/摘要 自动对接是获得分子机制理解的重要工具 相互作用是大多数生物过程的基础。它支持各种生物医学应用 从药物和化学探针设计到研究化学途径和识别 癌症和代谢紊乱等疾病的治疗目标。面临的两大挑战 自动对接保留了大分子在配体上发生的构象变化 结合和对接多肽等高度灵活的配体，这一领域已经获得了很多 最近很感兴趣。大多数对接程序使用刚性的大分子模型，因为 计算复杂性呈指数级增长，与之相关的对接精度降低 受体的灵活性。在上一个奖项下，我们在对接方面取得了重大进展 灵活的受体。我们开发并发布了一个软件程序，使成功的交叉- 将柔性配体对接到具有多达14个柔性侧链的受体的载脂蛋白构象中， 并证明了降低受体内部能量对 评分功能提高了对接成功率。对于下一个奖项，我们建议：1)延长 用于描述可旋转键以外的配体构象变化的一组运动对象，以及 用于表示局部和全局受体主干运动的运动对象，例如柔性环 和领域运动；2)改进了现有的搜索技术，并开发了新的表示 3)对评分函数进行了标定和优化 在对接期间特别在对接受体灵活性的情况下使用；以及4)使 通过清晰的书面文档和直观的图形用户，软件是有用和可用的 接口。在该项目下编译的数据集也将免费提供给 社区，并为评估停靠方法提供基准。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 模块化、基于组件的软件环境，具有可插拔的搜索技术和评分 函数，以及一组可扩展的分子柔性描述符。这款新的对接引擎将 成为广泛使用和流行的软件套件AutoDock的一部分。它将在世界上使用 社区网格，在治疗上重要的目标上的大虚拟屏幕。有能力 在对接模拟中包括受体灵活性将扩大生物学问题的范围 其中自动对接可以成功应用。因此，它将影响许多人的研究 药物化学家和生物学家，并将计算工具的使用扩展到更广泛的社区 从而支持生物医学研究的进步。

Project Summary/Abstract Automated docking is an important tool for gaining a mechanistic understanding of the molecular interactions underpinning most biological processes. It supports biomedical applications ranging from drug and chemical probes design to investigating chemical pathways and identifying therapeutic targets for diseases such as cancer and metabolic disorders. Two major challenges for automated docking remain the conformational changes occurring in macromolecules upon ligand binding and the docking highly flexible ligands such as peptides, an area that has gained a lot of interest recently. Most docking programs use rigid models of macromolecules because of the exponential increase of computational complexity and the decreased docking accuracy associated receptor flexibility. Under the previous award, we made significant progress towards docking with flexible receptors. We developed and released a software program allowing the successful cross- docking of flexible ligands into apo conformations of receptors with up to 14 flexible side-chains, and demonstrated that down-weighting the contribution of the receptor internal energy to the scoring function increased docking success rates. For the next award, we propose to: 1) extend the set of motion objects for describing ligand conformational changes beyond rotatable bonds, and motion objects for representing local and global receptor backbone motions such as flexible loops and domain motions; 2) enhance our current search technique and develop a new representation and associate search technique for docking peptides; 3) calibrate and optimize the scoring function sused during docking specifically in the context of docking with receptor flexibility; and 4) make the software useful and usable through clearly written documentation and intuitive graphical user interfaces. Datasets compiled under this project will also be made freely 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 with pluggable search techniques and scoring functions, and an extensible set of molecular flexibility descriptors. This new docking engine will be part of the widely used and popular software suite AutoDock. It will be used on the World Community Grid for large virtual screens on therapeutically important targets. The ability to include receptor flexibility in docking simulations will extend the range of biological problems for which automated docking can be successfully applied. Hence, it will impact the research of many medicinal chemists and biologist, and extend the use of computational tools to a wider community of scientists thereby supporting the advancement of biomedical research.