Flexible Macromolecular Docking

蛋白质与组分相互作用的三维结构的预测 构象变形和结合后的部分重构是一个巨大的挑战。它代表着一种 在对生物功能和疾病的现代结构理解中的主要瓶颈。合奏 对接作为一种实用方法出现，用于整合系统一部分的构象可变性。 使用系统遗漏扫描和/或局部相关正常生成集合的创新方法 模式是我们团队最近开发的，并在小分子对接中进行了测试。这些方法表明 在以前无法解决的情况下，令人鼓舞的结果，并可直接转移到蛋白质对接。 在本方案中，这些方法将被扩展并应用于蛋白质对接，包括 难以对接完全无结构的孤立或末端多肽。首先，构象系综论 通过引入新的4D对接程序，原子将极大地加快速度 具有完全灵活部件的模型将在一次运行中对接成同时呈现多个构型 菲尔兹。其次，将应用更快、更严格的全原子解决方案精化协议。这 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 将公开制定的蛋白质和多肽相互作用的全面诱导FIT基准 可用并定期更新。最后，拟议的对接协议将包括电子显微镜 (Em)数据和其他实验限制。一种新的阻尼动力学柔性拟合法设计 EM拟合将得到进一步的发展。 新的蛋白质和多肽对接方法和多域EM拟合法将应用于 通过合作的实验实验室解决生物学问题。蛋白质和蛋白质的结构预测 多肽复合体将导致发现和表征可作为靶点的新位点 小分子疗法。

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.