A MULTISTAGE APPROACH TO PROTEIN-PROTEIN DOCKING

傅立叶相关技术是一种非常有效的对接边界 (i.e.,共结晶的）蛋白质构象 互补性作为目标函数。然而，当对接未绑定（即， 独立结晶）构象，该方法产生了大量的 假阳性（即，具有良好分数但大RMSD的构象）。的 这个建议的主要目标是增加后处理步骤的傅立叶 对接算法，以消除所有误报。后处理将 包括刚体滤波器以减少候选结构的数量， 消除所有远离天然构象的灵活过滤器（使用RMSD 超过10 A），以及灵活的对接算法来细化剩余的几个。的 过滤和细化步骤利用不断变化的贡献， 静电学、去溶剂化和分子力学在不同的 蛋白质-蛋白质缔合和对接的阶段。刚体分析 是基于静电和去溶剂化之间的相互作用的映射 遇到复合物中的蛋白质;即，在广泛的表面接触之前， 确立了习这些相互作用对结构的敏感性要小得多。 扰动比表面互补性的措施，并提供了一个 有用的评分功能。然而，由于侧链的差异， 结合态和非结合态之间的构象，在 刚体分析，判别不完善，不能消除 都是假阳性包含分子力学和解释 灵活性产生显著的改善。特别是，在广泛的 分子力学结构的最小化，货车德瓦耳斯的总和， 静电和溶剂化/熵能项，不仅区分 近天然构象从诱饵在所有系统的研究，但也提供了 一个相对较好的排名近原生结构。这些初步结果 支持中心假设，即所有假阳性都可以消除， 保持和改善良好的对接构象。的效率 通过预处理步骤进一步增加整个对接算法，预处理步骤 或者试图改善表面侧链的构象，或者 引入非均匀高斯模糊以避免虚假重叠。 一个自动程序相结合的傅立叶对接程序与后， 预处理步骤将为应用程序提供强大的研究工具， 目前无法通过计算方法解决。

Fourier correlation techniques are very efficient for docking bound (i.e., co-crystallized) protein conformations using measures of surface complementarity as the target function. However, when docking unbound (i.e., independently crystallized) conformations, the method yields an enormous number of false positives (i.e., conformations with good score but large RMSD). The major goal of this proposal is to add post-processing steps to the Fourier docking algorithm in order to remove all false positives. Post-processing will include a rigid-body filter to reduce the number of candidate structures, a flexible filter that eliminates all far-from-native conformations (with RMSDs over 10 A), and a flexible docking algorithm to refine the remaining few. The filtering and refinement steps utilize the changing contributions that electrostatics, desolvation, and molecular mechanics exhibit at the different stages of both protein-protein association and docking. The rigid body analysis is based on the mapping of electrostatic and desolvation interactions between proteins in encounter complexes; i.e., before extensive surface contacts are established. These interactions are much less sensitive to structural perturbations than the measures of surface complementarity, and provide a useful scoring function. However, due to the differences in side chain conformations between bound and unbound states, within the framework of the rigid body analysis, the discrimination is not perfect, and cannot eliminate all false positives. Inclusion of molecular mechanics and accounting for flexibility yield dramatic improvement. In particular, after extensive molecular mechanics minimization of the structures, the sum of van der Waals, electrostatic, and solvation/entropic energy terms, not only discriminates the near-native conformations from decoys in all systems studied, but also provides a relatively good ranking of near-native structures. These preliminary results support the central hypothesis that all false positives can be removed while retaining and improving the good docked conformations. The efficiency of the entire docking algorithm is further increased by pre-processing steps that either attempt to improve the conformations of surface side chains, or introduce a nonuniform Gaussian blurring in order to avoid spurious overlaps. An automatic procedure combining Fourier docking programs with the post- and pre-processing steps will provide a powerful research tool in applications that currently cannot be addressed by computational methods.