A Multistage Approach to Protein-Protein Docking

描述（由申请人提供）：傅立叶相关技术对于使用表面互补性的测量作为目标函数的蛋白质对接非常有效。然而，除了近天然构象之外，该方法还产生大量的假阳性（即，具有良好分数但大RMSD的构象）。已经取得了实质性的进展，在开发后处理方法，可以排名对接的构象和选择接近的天然，但刚性体性质的蛋白质对接仍然是一个限制。后处理有助于如果有一个很强的形状互补性，如在酶抑制剂复合物。然而，在抗体-抗原和许多其他复合物中，界面的填充不太好，其中极性相互作用和盐桥对于结合更重要。对于这些复合物，傅立叶相关技术产生较少的命中，歧视的近天然对接结构变得困难，由于较低的亲和力，结果是非常敏感的小扰动的组件蛋白质的坐标。这个建议的总体目标是扩展多级对接的能力，使其超出主要由形状互补性稳定的复合物。这将通过以下方式实现：（1）基于对接构象的聚类，开发稳健的鉴别方法;（2）同时灵活细化保留的簇，这将能够发现和细化甚至低质量的命中;（3）基于来自具有明确溶剂的纳秒分子动力学模拟的构象统计，调整最重要的表面侧链的构象;和（4）通过整合来自在前一步骤中已经产生的多个蛋白质结构的对接的结果，并且因此在一些关键侧链的构象上不同。初步结果表明，这些策略将大大提高对接结果相对较弱的复合物，经常发挥重要作用，在免疫识别，信号转导和细胞周期控制。

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.