A multistage approach to protein-protein docking

蛋白质-蛋白质对接的多阶段方法

• 批准号: 8213667
• 负责人: SANDOR VAJDA
• 金额: $ 26.12万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213667
• 关键词: Accounting; Address; Adopted; Algorithms; Amino Acids; Antibodies; Antigen-Antibody Complex; Antigens; Area; Binding; Biophysics; Collaborations; Communities; Complex; Consensus; Data; Development; Dimensions; Discrimination; Docking; Electrostatics; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epitopes; Fourier Transform; Fox Chase Cancer Center; Free Energy; Freedom; Gene Expression Regulation; Goals; Graph; Health; Hydrogen Bonding; Hydrophobicity; Institutes; Libraries; Ligands; Metabolic Control; Methodology; Methods; Molecular Conformation; Online Systems; Paper; Pattern; Process; Property; Proteins; Publishing; Radial; Relative (related person); Research; Resolution; Rotation; Sampling; Shapes; Side; Signal Transduction; Site-Directed Mutagenesis; Solvents; Specific qualifier value; Speed; Staging; Structure; Sum; Surface; Techniques; Transduction Gene; Translations; Update; Visit; Weight; Writing; X-Ray Crystallography; anticancer research; base; cost; crosslink; experimental analysis; flexibility; improved; improved functioning; molecular dynamics; novel; programs; protein complex; protein protein interaction; receptor; research study; statistics; stem; theories

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.

描述（由申请人提供）：研究蛋白质-蛋白质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、短暂的复合物中，这些复合物不适合直接的实验分析，即使相互作用的蛋白质都可以被分离出来并确定它们的结构。因此，开发从组成蛋白的结构出发，以接近x射线晶体学的精度确定其复合物结构的计算对接方法是很重要的。我们的多阶段对接方法从刚体搜索开始，使用快速傅里叶变换（FFT）相关计算对网格上的数十亿个构象进行采样，并包括后处理，以在数千个对接结构中找到接近原生的构象。在最新的CAPRI对接实验中，我们的方法是最好的，但对于抗原-抗体和其他一些类型的复合物，我们的结果仍然很差。本提案的总体目标是开发新的算法，以提高多级对接的准确性和可靠性，同时保持其计算效率，从而使基于web的对接服务器能够使用最先进的方法。着力解决三个问题。首先，基于蒙特卡罗的对接程序已经证明，在界面中搜索最优侧链构象可以改善结果。然而，蒙特卡罗算法并不是一种非常有效的搜索方法，而且这种程序的计算量太大，无法在没有先验结构信息的情况下全局地探索构象空间。为了解决这个问题，我们将在多阶段方法的框架内开发高效的特定于对接的侧链搜索算法。这将包括识别对识别最重要的“关键”侧链，从而降低侧链的自由度。其次，考虑到静电、脱溶、氢键和可能的实验约束，可以改善对接结果，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fft的多属性5维算法来重新获得这一优势，该算法可以用于任意复杂性的评分函数，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电位，可以大大改善结果，这可以解释特定类别的蛋白质-蛋白质复合物相互作用的生物物理学。在项目的前六个月，我们建立了一个新版本的ClusPro服务器，实验人员大量使用，它将包括最近的发展。当我们的新算法可用时，服务器将不断更新。除了提供服务器之外，我们已经开始开发针对对接问题的模块化程序库，该程序库将免费提供。公共卫生相关性：研究蛋白质-蛋白质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。由于许多生物学上重要的相互作用发生在弱的、瞬态的复合物中，不适合直接的实验分析，因此开发计算对接方法非常重要，该方法可以从组分蛋白的结构开始，以接近x射线晶体学的精度确定其复合物的结构。本方案的总体目标是进一步提高多级对接的精度，同时保持其计算效率，从而使科学界能够使用最先进的方法在蛋白质对接服务器中进行对接。