Macromolecular Docking

描述（由申请人提供）：蛋白质相互作用几何结构的可靠和有效预测仍然是一个未解决的问题。然而，它是未来结构生物学的关键技术。我们的长期目标是开发可靠的蛋白质对接预测程序，以促进我们对生物体中发生的复杂调控和代谢过程的结构理解，并设计用于阻断或修饰这些相互作用的药物。目前的对接技术存在两个主要瓶颈。首先，两种蛋白质在缔合时经历诱导的构象变化，而目前的方法不能充分处理这种灵活性。第二，对接过程的初始阶段，所谓的刚体对接，太慢而不能考虑多种受体和配体构象。我们的主要目标是克服这些瓶颈，并开发新的方法来预测对接的蛋白质经历骨架变形。 第一次对蛋白质相互作用预测的批判性评估（卡普里）的结果显示，在处理诱导拟合方面有一些适度但有希望的迹象。在这里，我们建议进一步发展对接方法，结合最近的密度匹配算法，在小分子对接的最新成果，以及通过找到一种有效的方法来处理侧链和骨架的灵活性。 为了加快刚体对接的速度，我们将采用一种新的五维快速傅立叶变换方法，用于同时确定蛋白质对接的旋转和平移。这将导致快速生成试验解决方案，并允许探索相互作用伙伴的多种构象。其次，新的试验解决方案重新评分计划和更好的网格电位图所使用的5DFFT方法将开发和优化的基准上已知的复杂。第三，将开发更好的方法来处理显式蛋白质侧链柔性。最后，我们将研究的现象，骨干重排后的协会和预测多个构象的刚体对接，以及纳入重排的细化过程。新出现的程序将应用于生物问题，并在卡普里对接比赛中进行测试。

DESCRIPTION (provided by applicant): Reliable and efficient predictions of protein interaction geometry remains an unsolved problem. Yet it is a key technology for the structural biology of the future. Our long term goal is to develop reliable protein docking prediction procedures to facilitate our structural understanding of the complex regulatory and metabolic processes that occur in living organisms, and to enable design of drugs for blocking or modifying these interactions. There are two principal bottlenecks in the current docking technology. Firstly, two proteins undergo induced conformational changes upon association, while the current methods cannot adequately deal with such flexibility. Secondly, the initial phase of the docking procedure, so called rigid body docking, is too slow to consider multiple receptor and ligand conformations. Our main goal is to overcome these bottlenecks and develop new methods to predict docking of proteins undergoing backbone deformations. The results of the first Critical Assessment of PRotein Interaction predictions (CAPRI) revealed some modest but hopeful signs in dealing with the induced fit. Here we propose to further develop the docking methodology by incorporating recent density matching algorithms, the latest achievements in small molecule docking, as well as by finding an efficient way to deal with both side-chain and backbone flexibility. To speed up the rigid body docking we will adapt a new Five Dimensional Fast Fourier Transform method for simultaneous determination of rotation and translation to protein docking. This will lead to a quick generation of trial solutions and will allow exploring multiple conformations of the interacting partners. Secondly, new trial solution re-scoring schemes and better grid potential maps used by the 5DFFT method will be developed and optimized on a benchmark of known complexes. Thirdly, better ways to treat explicit protein side-chain flexibility will be developed. Finally, we will study the phenomenon of backbone rearrangements upon association and predict multiple conformations for rigid body docking, as well as incorporate the rearrangements into refinement procedure. The emerging procedures will be applied to biological problems and tested in the CAPRI docking competition.