Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein-Protein Binding Affinity upon Mutation
Flex ddG: Rosetta Ensemble-Based Estimation of Changes in Protein-Protein Binding Affinity upon Mutation
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DOI：
10.1021/acs.jpcb.7b11367
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发表时间：
2018-05-31
影响因子：
3.3
通讯作者：
Kortemme, Tanja
中科院分区：
文献类型：
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作者：
Barlow, Kyle A.;Conchuir, Shane O.;Kortemme, Tanja
突变后结合自由能的计算建模变化（界面三角洲g）允许对蛋白质 - 蛋白质相互作用的大规模预测和扰动。另外，考虑和采样相关构象可塑性的方法应能够实现与不能的方法相对于方法的更高预测准确性。为了检验这一假设，我们在Rosetta大分子建模套件（FLEX DDG）中开发了一种方法，该方法使用“ Backrub”样本构象多样性来生成模型集合，然后应用最小化的扭转，侧链重新添加，并在此集合中进行平均估算接口三角洲g值。我们在精选的1240个突变体的基准集上测试了我们的方法，并发现该方法的表现优于将构象空间采样较小程度的现有方法。我们观察到了flex DDG比现有方法在小侧链对大侧链突变的子集的子集以及多个同时非丙氨酸突变，稳定突变和抗体 - 抗原界接口中的突变的情况下进行了显着改善。最后，我们将广义添加剂模型（GAM）方法应用于Rosetta能量函数。由此产生的非线性重新加权模型通过实验确定的界面三角洲G值改善了一致性，但也强调了未来能量函数改进的必要性。
Computationally modeling changes in binding free energies upon mutation (interface Delta Delta G) allows large-scale prediction and perturbation of protein-protein interactions. Additionally, methods that consider and sample relevant conformational plasticity should be able to achieve higher prediction accuracy over methods that do not. To test this hypothesis, we developed a method within the Rosetta macromolecular modeling suite (flex ddG) that samples conformational diversity using "backrub" to generate an ensemble of models and then applies torsion minimization, side chain repacking, and averaging across this ensemble to estimate interface Delta Delta G values. We tested our method on a curated benchmark set of 1240 mutants, and found the method outperformed existing methods that sampled conformational space to a lesser degree. We observed considerable improvements with flex ddG over existing methods on the subset of small side chain to large side chain mutations, as well as for multiple simultaneous non-alanine mutations, stabilizing mutations, and mutations in antibody-antigen interfaces. Finally, we applied a generalized additive model (GAM) approach to the Rosetta energy function; the resulting nonlinear reweighting model improved the agreement with experimentally determined interface Delta Delta G values but also highlighted the necessity of future energy function improvements.