A multistage approach to protein-protein docking

描述(申请人提供)：研究蛋白质之间的相互作用对于更好地理解代谢控制、信号转导和基因调控等过程至关重要。许多生物学上重要的相互作用发生在弱的、瞬时的复合体中，即使可以分离出两种相互作用的蛋白质并确定它们的结构，这些复合体也不能直接进行实验分析。因此，开发计算对接方法非常重要，这种方法可以从组分蛋白质的结构出发，以接近X射线结晶学的精度确定其络合物的结构。我们的多阶段对接方法从刚体搜索开始，使用快速傅立叶变换(FFT)相关计算对网格上的数十亿构象进行采样，并包括后处理，以在数千个对接结构中找到接近自然的构象。在最新的Capri对接实验中，我们的方法是最好的之一，但对于抗原-抗体和其他一些类型的络合物来说，结果仍然很差。这项提议的总体目标是开发新的算法，在保持其计算效率的同时提高多级对接的准确性和可靠性，从而使基于网络的对接服务器能够使用最先进的方法。我们将解决三个问题。首先，基于蒙特卡罗的对接程序已经证明，在界面上寻找最佳侧链构象可以改善结果。然而，蒙特卡罗并不是一个非常有效的搜索，而且这样的程序在计算上要求太高，在没有关于复合体结构的先验信息的情况下无法全局地探索构象空间。为了纠正这一点，我们将在多阶段方法的框架内开发有效的对接特定侧链搜索算法。这将包括识别对识别最重要的“关键”侧链，从而减少侧链的自由度。其次，考虑到静电、去溶、氢键和可能的实验限制，改善了对接结果，但使用这种复杂的评分函数会降低FFT相关方法提供的数值优势。我们将通过开发一种基于多属性五维FFT的算法来重新获得这一优势，该算法可以与任意复杂性的评分函数一起使用，而不会增加计算成本。第三，抗体-抗原对的对接效果特别差。我们的初步数据表明，通过采用不对称疏水性势来解释特定类型的蛋白质-蛋白质复合体中相互作用的生物物理，可以显著改善结果。在项目的前六个月，我们设置了ClusPro服务器的新版本，实验者大量使用，其中将包括最新的开发。当我们的新算法可用时，服务器将不断更新。除了提供服务器，我们已经开始开发专门针对对接问题的模块化程序库，可以免费访问。公共卫生相关性：研究蛋白质-蛋白质相互作用对于更好地了解代谢控制、信号转导和基因调控等过程至关重要。由于许多生物上重要的相互作用发生在不能直接进行实验分析的微弱的瞬时络合物中，因此开发计算对接方法非常重要，这种方法可以从组分蛋白质的结构出发，以接近X射线结晶学的精度确定其络合物的结构。这项提议的总体目标是在保持其计算效率的同时进一步提高多级对接的准确性，从而使科学界可以在蛋白质对接服务器中使用最先进的方法。

DESCRIPTION (provided by applicant): Studying protein-protein interactions is crucial to gaining a better understanding of processes such as metabolic control, signal transduction, and gene regulation. Many biologically important interactions occur in weak, transient complexes that are not amenable to direct experimental analysis, even if both interacting proteins can be isolated and their structures determined. Thus it is important to develop computational docking methods that, starting from the structures of component proteins, can determine the structure of their complexes with accuracy close to that obtained by X-ray crystallography. Our multistage approach to docking starts with a rigid body search that samples billions of conformations on a grid using fast Fourier transform (FFT) correlation calculations, and includes post-processing to find near-native conformations among thousands of docked structures. Our methods were among the best in the latest CAPRI docking experiment, but results are still poor for antigen-antibody and some other types of complexes. The general goal of this proposal is the development of new algorithms that will improve the accuracy and reliability of multistage docking while retaining its computational efficiency, hence enabling the use of state-of- the-art methods for a web-based docking server. We will address three problems. First, Monte Carlo-based docking programs have demonstrated that searching for optimal side chain conformations in the interface can improve results. However, Monte Carlo is not a very efficient search, and such programs are computationally too demanding to globally explore the conformational space without a priori information on the structure of the complex. To remedy this we will develop efficient docking-specific side chain search algorithms within the framework of the multistage approach. This will include the identification of "key" side chains that are most important for recognition, thereby reducing the side chains' degrees of freedom. Second, accounting for electrostatics, desolvation, hydrogen bonding, and possibly experimental constraints improves docking results, but the use of such complex scoring functions reduces the numerical advantage provided by the FFT correlation approach. We will regain this advantage by developing a multi-property 5-dimensional FFT-based algorithm that can be used with scoring functions of arbitrary complexity without added computational costs. Third, docking results are particularly poor for antibody-antigen pairs. Our preliminary data indicate that results can be substantially improved by adopting asymmetric hydrophobicity potentials that account for the biophysics of interactions in particular classes of protein-protein complexes. In the first six months of the project we set up a new version of our ClusPro server, heavily used by experimentalists, which will include recent developments. The server will be continuously updated as our new algorithms become available. In addition to providing the server, we have already started development on a modular program library specific to the docking problem that will be freely accessible. PUBLIC HEALTH RELEVANCE: Studying protein-protein interactions is crucial to gaining a better understanding of processes such as metabolic control, signal transduction and gene regulation. Since many biologically important interactions occur in weak, transient complexes that are not amenable to direct experimental analysis, it is important to develop computational docking methods that, starting from the structures of component proteins, can determine the structure of their complexes with accuracy close to that obtained by X-ray crystallography. The general goal of this proposal is to further improve the accuracy of multistage docking while retaining its computational efficiency, thereby enabling the use of state-of-the-art methods in protein docking servers available to the scientific community.