物理化学学报 >> 2010, Vol. 26 >> Issue (07): 1988-1997.doi: 10.3866/PKU.WHXB20100725

生物物理化学 上一篇    下一篇

蛋白质相互作用: 界面分析, 结合自由能计算与相互作用设计

白红军, 来鲁华   

  1. 北京大学化学与分子工程学院, 分子动态与稳态结构国家重点实验室, 北京分子科学国家实验室, 北京 100871
    北京大学理论生物学中心, 北京 100871
  • 收稿日期:2010-03-30 修回日期:2010-05-13 发布日期:2010-07-02
  • 通讯作者: 来鲁华 E-mail:lhlai@pku.edu.cn

Protein-Protein Interactions: Interface Analysis, Binding Free Energy Calculation and Interaction Design

BAI Hong-Jun, LAI Lu-Hua   

  1. Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Structural Chemistry for Stable and Unstable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China
    Center for Theoretical Biology, Peking University, Beijing 100871, P. R. China
  • Received:2010-03-30 Revised:2010-05-13 Published:2010-07-02
  • Contact: LAI Lu-Hua E-mail:lhlai@pku.edu.cn

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摘要：

蛋白质相互作用在生命活动中起着重要作用. 研究蛋白质间相互作用的本质有助于了解生命活动中这些基本单元的作用. 本文主要综述了近期蛋白质相互作用研究的进展, 包括蛋白质相互作用界面的基本性质, 蛋白质结合自由能的计算方法, 不同相互作用在蛋白质结合/解离中的角色和差异, 以及上述知识在蛋白质相互作用设计中的应用. 蛋白质相互作用界面的特性, 例如界面大小、保守性以及结构的动态性质, 使得具有生物功能的蛋白质相互作用界面区别于非特异性的晶体堆积界面. 生物功能界面的一个重要结构特征是界面上存在着关键残基以及相对独立的相互作用模块. 利用多种方法, 如MM-PBSA、统计平均势以及不同的相互作用自由能模型, 可以在不同的精度上计算蛋白质相互作用自由能. 利用蛋白质相互作用界面的特点, 从不同的角度进行蛋白质相互作用对的设计与改造, 近年来已经有了不少成功的例子, 但还存在着很大的挑战. 我们认为在今后的蛋白质相互作用设计中, 考虑各种因素对蛋白质结合与解离的动力学过程的影响将有助于提高人类控制蛋白质相互作用的能力.

关键词: 蛋白质相互作用, 界面性质, 界面结构特征, 结合自由能计算, 蛋白质相互作用设计, 蛋白质结合/解离

Abstract:

Protein-protein interactions (PPI) play essential roles in biological processes. Understanding PPI from a structural, thermodynamic, and kinetic point of view gives us a better understanding about these building blocks of living systems. This review summarizes the recent progresses in PPI research, including the basic properties of the interfaces, different methods for the calculation of binding free energies, key determinants in the kinetic process of PPI, and successful examples of PPI design. Interfaces of specific biological protein complexes are distinct from non-specific crystal packing interfaces in many aspects, such as the interfacial size, the conservation of amino acid residues, and structural dynamic properties. Hotspots, hot regions, and modular structures can be found at the biological PPI interface. The binding free energy of PPI can be calculated using different approaches, such as MM-PBSA, potential of mean force, and various free energy models, based on structures of protein complexes. Various approaches and successes have been reported for new PPI design based on current knowledge, however, much needs to be done to further improve the manipulation of diverse PPI. We propose that the protein association/dissociation kinetic process should be considered in future PPI design studies, which may provide more options for the manipulation and engineering of PPI.

Key words: Protein-protein interactions, Basic property of protein-protein interfaces, Structural feature of protein-protein interfaces, Binding free energy calculation, Protein-protein interaction design, Protein-protein association/dissociation