• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Molecular Biology >Predicting the Effect of Amino Acid Single-Point Mutations on Protein Stability Large-Scale Validation of MD-Based Relative Free Energy Calculations
【24h】

Predicting the Effect of Amino Acid Single-Point Mutations on Protein Stability Large-Scale Validation of MD-Based Relative Free Energy Calculations

机译：预测氨基酸单点突变对蛋白质稳定性大规模验证MD基相对能量计算的影响

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The stability of folded proteins is critical to their biological function and for the efficacy of protein therapeutics. Predicting the energetic effects of protein mutations can improve our fundamental understanding of structural biology, the molecular basis of diseases, and possible routes to addressing those diseases with biological drugs. Identifying the effect of single amino acid point mutations on the thermodynamic equilibrium between the folded and unfolded states of a protein can pinpoint residues of critical importance that should be avoided in the process of improving other properties (affinity, solubility, viscosity, etc.) and suggest changes at other positions for increasing stability in protein engineering. Multiple computational tools have been developed for in silico predictions of protein stability in recent years, ranging from sequence-based empirical approaches to rigorous physics-based free energy methods. In this work, we show that FEP+, which is a free energy perturbation method based on all-atom molecular dynamics simulations, can provide accurate thermal stability predictions for a wide range of biologically relevant systems. Significantly, the FEP+ approach, while originally developed for relative binding free energies of small molecules to proteins and not specifically fitted for protein stability calculations, performs well compared to other methods that were fitted specifically to predict protein stability. Here, we present the broadest validation of a rigorous free energy-based approach applied to protein stability reported to date: 700+ single-point mutations spanning 10 different protein targets. Across the entire data set, we correctly classify the mutations as stabilizing or destabilizing in 84% of the cases, and obtain statistically significant predictions as compared with experiment [average error of similar to 1.6 kcal/mol and coefficient of determination (R-2) of 0.40]. This study demonstrates, for the first time in a large-scale validation, that rigorous free energy calculations can be used to predict changes in protein stability from point mutations without parameterization or system-specific customization, although further improvements should be possible with additional sampling and a better representation of the unfolded state of the protein. Here, we describe the FEP+ method as applied to protein stability calculations, summarize the large-scale retrospective validation results, and discuss limitations of the method, along with future directions for further improvements. (C) 2016 Elsevier Ltd. All rights reserved.
机译：折叠蛋白的稳定性对其生物学功能和蛋白质治疗剂的疗效至关重要。预测蛋白质突变的能量效应可以改善我们对结构生物学的基本理解，疾病的分子基础以及可能的途径，以解决具有生物药物的这些疾病。鉴定单氨基酸点突变对蛋白质的折叠和展开状态之间的热力学平衡的影响，可以针对应避免在改善其他性质（亲和力，溶解度，粘度等）的过程中避免的临界重要性的残留物。建议在蛋白质工程中提高稳定性的其他位置的变化。近年来，在近年来蛋白质稳定性的硅预测中开发了多种计算工具，从基于序列的实证方法到基于严格的物理学的自由能方法。在这项工作中，我们表明FEP +是基于全原子分子动力学模拟的自由能扰动方法，可以为广泛的生物相关系统提供准确的热稳定性预测。值得注意的是，FEP +方法，虽然最初为小分子与蛋白质的相对结合能量而言而不是用于蛋白质稳定性计算，但与特异性地预测蛋白质稳定性的其他方法相比表现良好。在这里，我们展示了迄今为止报告的蛋白质稳定性的严格自由能量的方法的最广泛验证：700多个单点突变跨越10种不同的蛋白质靶标。在整个数据集中，我们在84％的情况下正确地将突变分类为稳定或稳定化，并且与实验相比，获得统计学上的预测[平均误差与1.6千卡/摩尔和摩尔系数和测定系数（R-2）相比0.40]。本研究表明，在大规模的验证中，可以使用严格的自由能量计算来预测从点突变的蛋白质稳定性的变化，而无需参数化或系统特定的定制，尽管应该使用额外的采样和额外的采样来实现进一步的改进更好地表示蛋白质的展开状态。在这里，我们描述了应用于蛋白质稳定性计算的FEP +方法，总结了大规模回顾性验证结果，并讨论该方法的限制以及未来的进一步改进方向。 （c）2016 Elsevier有限公司保留所有权利。

著录项

  • 来源
    《Journal of Molecular Biology》 |2017年第7期|共16页
  • 作者

    Steinbrecher Thomas; Zhu Chongkai; Wang Lingle; Abel Robert; Negron Christopher; Pearlman David; Feyfant Eric; Duan Jianxin; Sherman Woody;

  • 作者单位

    Schrodinger GmbH Dynamostr 13 D-68165 Mannheim Germany;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

    Schrodinger GmbH Dynamostr 13 D-68165 Mannheim Germany;

    Schrodinger Inc 120 West 45th St 17th Floor New York NY 10036 USA;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号