Efficient determination of protein-protein standard binding free energies from first principles.
Efficient determination of protein-protein standard binding free energies from first principles.
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DOI：
10.1021/ct400273t
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发表时间：
2013-08-13
影响因子：
5.5
通讯作者：
Chipot, Christophe
中科院分区：
文献类型：
--
作者：
Gumbart, James C.;Roux, Benoit;Chipot, Christophe
定量表征蛋白质-蛋白质关联一直是计算机模拟的一个长期挑战。本文提出了一个理论框架，在详细的全原子分子动力学模拟的基础上，通过显式溶剂来解决这一挑战。所提出的方法依赖于依次进行的独立平均力势（PMF）自由能计算，其中生物对象被限制在结合态的构象、位置和方向上，使用适当选择的偏置势。这些限制系统地缩小了系统可用的构型熵，并有效地保证了当两种蛋白质可逆结合时，相关的相互作用网络被正确采样。将结合过程分解为连续的、描述良好的阶段，对于蛋白质复合物和单独的、未结合的伙伴，提供了标准状态的严格定义，从中可以确定绝对结合自由能。该方法适用于胞外核糖核酸酶barnase与胞内抑制剂barstar结合的困难情况。计算得到的结合自由能为- 21.0±1.4 kcal/mol，与实验值- 19.0±0.2 kcal/mol比较吻合。相对较小的统计误差反映了基于pmf的仿真方法的精度和收敛性。除了提供标准结合自由能的精确再现外，所提出的策略还提供了蛋白质-蛋白质界面的详细图像，阐明了可逆结合背后的热力学力。目前形式框架的应用，以barnase:barstar结合提供了一个基础，处理几乎任何蛋白质-蛋白质复合物。
Characterizing protein-protein association quantitatively has been a longstanding challenge for computer simulations. Here, a theoretical framework is put forth that addresses this challenge on the basis of detailed all-atom molecular dynamics simulations with explicit solvent. The proposed methodology relies upon independent potential of mean force (PMF) free-energy calculations carried out sequentially, wherein the biological objects are restrained in the conformation, position and orientation of the bound state, using adequately chosen biasing potentials. These restraints systematically narrow down the configurational entropy available to the system and effectively guarantee that the relevant network of interactions is properly sampled as the two proteins reversibly associate. Decomposition of the binding process into consecutive, well-delineated stages, for both the protein complex and the individual, unbound partners, offers a rigorous definition of the standard state, from which the absolute binding free energy can be determined. The method is applied to the difficult case of the extracellular ribonuclease barnase binding to its intracellular inhibitor barstar. The calculated binding free energy is −21.0 ± 1.4 kcal/mol, which compares well with the experimental value of −19.0 ± 0.2 kcal/mol. The relatively small statistical error reflects the precision and convergence afforded by the PMF-based simulation methodology. In addition to providing an accurate reproduction of the standard binding free energy, the proposed strategy offers a detailed picture of the protein-protein interface, illuminating the thermodynamic forces that underlie reversible association. The application of the present formal framework to barnase:barstar binding provides a foundation for tackling nearly any protein-protein complex.
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影响因子：
64.8
作者：
CHOTHIA, C;JANIN, J
通讯作者：
JANIN, J
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
DOI：
10.1021/jp807701h
发表时间：
2009-02-26
期刊：
The journal of physical chemistry. B
影响因子：
--
作者：
Deng Y;Roux B
通讯作者：
Roux B
影响因子：
5.5
作者：
Gumbart, James C.;Roux, Benoit;Chipot, Christophe
通讯作者：
Chipot, Christophe
影响因子：
64.8
作者：
Cheng, YK;Rossky, PJ
通讯作者：
Rossky, PJ