Expanding molecular modeling and design tools to non-natural sidechains
Expanding molecular modeling and design tools to non-natural sidechains
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DOI：
10.1002/jcc.22982
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发表时间：
2012-07-05
影响因子：
3
通讯作者：
Zoete, Vincent
中科院分区：
文献类型：
--
作者：
Gfeller, David;Michielin, Olivier;Zoete, Vincent
蛋白质-蛋白质相互作用编码了细胞信号通路的接线图，它们的失调是多种疾病（如癌症）的基础。用肽衍生物抑制蛋白质-蛋白质相互作用是开发新的生物学和治疗工具的一种有前途的方法。在这里，我们开发了一个通用框架来计算处理数百个非天然氨基酸侧链，并预测将它们插入肽或蛋白质的效果。我们首先生成所有的结构文件（PDB和MOL 2），以及标准分子力学软件（CHARMM和Gromacs）的参数和拓扑结构。旋转异构体概率的准确预测提供了一种新的组合知识和物理为基础的战略。非天然侧链可用于增加肽配体结合亲和力。我们的研究结果显示，非天然突变体的BCL 9肽靶向β-连环蛋白的预测和实验结合自由能之间有很好的相关性，这表明这种预测可用于设计新的抑制剂。在这项工作中生成的数据，以及PyMOL和UCSF Chimera插件，用于非天然侧链的用户友好可视化，都可以在。我们的研究结果使研究人员能够快速有效地处理数百种非天然侧链。(C)2012 Wiley Periodicals，Inc.
Proteinprotein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting proteinprotein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non-natural sidechains, are all available at . Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains. (C) 2012 Wiley Periodicals, Inc.