A Multistage Approach to Protein-Protein Docking

蛋白质-蛋白质对接的多阶段方法

• 批准号: 6826194
• 负责人: SANDOR VAJDA
• 金额: $ 24.23万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826194
• 关键词: antigen antibody reaction; binding sites; computer program /software; computer simulation; conformation; crystallization; model design /development; molecular dynamics; physical model; protein folding; protein protein interaction; protein structure function; structural biology

DESCRIPTION (provided by applicant): Fourier correlation techniques are very efficient for protein docking using measures of surface complementarity as the target function. However, in addition to near-native conformations, the method yields an enormous number of false positives (i.e., conformations with good score but large RMSD). Substantial progress has been made in developing post-processing methods that can rank the docked conformations and select the ones close to the native, but the rigid body nature of protein docking still remains a limitation. Post-processing helps if there is a strong shape complementarity as in enzyme-inhibitor complexes. However, the interface is less well-packed in antibody-antigen and many other complexes, in which polar interactions and salt bridges are more important for binding. For these complexes, Fourier correlation techniques produce fewer hits, discrimination of the near-native docked structures becomes difficult due to the lower affinity, and the results are very sensitive to small perturbations in the coordinates of the component proteins. The general goal of this proposal is to extend the power of multistage docking beyond the complexes primarily stabilized by shape complementarity. This will be achieved (1) by developing robust discrimination methods, based on the clustering of the docked conformations; (2) by simultaneous flexible refinement of the retained clusters that will be able to find and refine even low quality hits; (3) by adjusting the conformation of the most important surface side chains, based on conformational statistics from nanosecond molecular dynamics simulations with explicit solvent; and (4) by integrating results from the docking of multiple protein structures that have been generated in the previous step, and thus differ in the conformations of some key side chains. Preliminary results show that these strategies will substantially improve docking results for relatively weak complexes that frequently play important roles in immune recognition, signal transduction, and cell cycle control.

描述（由申请人提供）：傅里叶相关技术对于使用表面互补性测量作为目标函数的蛋白质对接非常有效。然而，除了接近天然的构象外，该方法还会产生大量误报（即得分良好但 RMSD 较大的构象）。在开发后处理方法方面已经取得了实质性进展，这些方法可以对对接构象进行排序并选择接近天然的构象，但蛋白质对接的刚体性质仍然是一个限制。如果酶-抑制剂复合物具有很强的形状互补性，则后处理会有所帮助。然而，抗体-抗原和许多其他复合物中的界面填充不太好，其中极性相互作用和盐桥对于结合更为重要。对于这些复合物，傅里叶相关技术产生的命中较少，由于亲和力较低，区分接近天然的对接结构变得困难，并且结果对组分蛋白质坐标的小扰动非常敏感。该提案的总体目标是将多级对接的能力扩展到主要由形状互补稳定的复合体之外。这将通过 (1) 基于对接构象的聚类开发强大的区分方法来实现； (2) 通过同时灵活地细化保留的簇，将能够找到并细化甚至低质量的命中； （3）基于显式溶剂纳秒分子动力学模拟的构象统计，通过调整最重要的表面侧链的构象； (4)整合上一步生成的多个蛋白质结构的对接结果，从而在一些关键侧链的构象上有所不同。初步结果表明，这些策略将大大改善相对较弱的复合物的对接结果，这些复合物经常在免疫识别、信号转导和细胞周期控制中发挥重要作用。