Flexible Macromolecular Docking

描述(申请人提供)：预测蛋白质与结合时发生构象变形和部分重组的成分的三维结构是一个巨大的挑战。它代表了对生物功能和疾病的现代结构理解的一个主要瓶颈。整体对接作为一种实用的方法出现，用于结合系统一部分的构象变化。我们小组最近开发了使用系统省略扫描和/或局部相关简正模式生成系综的创新方法，并在小配体对接中进行了测试。这些方法在以前无法解决的病例中显示了令人鼓舞的结果，并且可以直接转移到蛋白质对接上。在本提案中，这些方法将被扩展和应用于蛋白质对接，包括最困难的完全无结构的分离或末端多肽的对接。首先，通过引入新的4D对接程序，构象系综方法将大大加速，在该程序中，具有完全灵活部件的原子模型将在一次运行中对接到同时存在的多个构象场中。其次，将应用更快、更严格的全原子解决方案精化协议。该协议在软约束和完全灵活的接口补丁上运行。所有方法都将在一个全面的蛋白质和多肽相互作用的诱导匹配基准上进行测试，该基准将公开提供并定期更新。最后，建议的对接协议将包括电子显微镜(EM)数据和其他实验限制。进一步发展了一种新的用于电磁拟合的阻尼式动力学柔性拟合法。新的蛋白质和多肽对接方法和多域EM拟合法将与合作的实验实验室一起应用于解决生物学问题。蛋白质和多肽复合体的结构预测将导致发现和表征可作为小分子疗法靶点的新位点。 公共卫生相关性：预测柔性蛋白质和多肽的瞬时关联的三维结构是现代结构理解生物功能和疾病的主要瓶颈。我们建议通过使用治疗蛋白质柔韧性的新方法来克服这些主要障碍，并应用这些方法来发现分子治疗学发展的新靶点。

DESCRIPTION (provided by applicant): Prediction of the three-dimensional structure of protein associations with components that undergo conformational deformations and partial re-structuring upon binding is a great challenge. It represents a major bottleneck in the modern structural understanding of biological function and disease. Ensemble docking emerged as a practical approach for incorporating conformational variability of a part of the system. Innovative ways to generate the ensembles using systematic omission scans and/or local relevant normal modes were developed recently by our group and tested in small ligand docking. The methods showed encouraging results in previously unsolvable cases, and are directly transferable to protein docking. In the present proposal, these methods will be extended and applied to protein docking including the most difficult docking of fully unstructured isolated or terminal peptides. Firstly, the conformational ensemble approach will be dramatically accelerated by introducing a new 4D docking procedure in which atomic models with fully flexible parts will be docked in a single run into concurrently present multiple conformation fields. Secondly, a faster and more rigorous all-atom solution refinement protocol will be applied. This protocol operates on softly restrained and fully flexible interface patches. All methods will be tested on a comprehensive induced fit benchmark for protein and peptide interactions that will be made publically available and regularly updated. Finally, the proposed docking protocol will incorporate electron microscopy (EM) data and other experimental restraints. A new damped dynamics flexible fitting method designed for EM fitting will be further developed. The new protein and peptide docking methods and multi domain EM fitting methods will be applied to solving biological problems with collaborating experimental laboratories. Structure prediction of protein and peptide complexes will lead to the discovery and characterization of new sites that can be targeted with small molecule therapeutics. PUBLIC HEALTH RELEVANCE: Prediction of the three-dimensional structure of transient associations of flexible proteins and peptides represents a major bottleneck for modern structural understanding of biological function and disease. We proposed to overcome these major hurdles by using new methods for treating protein flexibility, and apply these methods to discover new targets for the development of molecular therapeutics.