Sequence-specific DNA binding transcription factors play an essential role in the transcriptional regulation of all organisms. The development of reliable in silico methods to predict the binding affinity landscapes of transcription factors thus promises to provide rapid screening of transcription factor specificities and, at the same time, yield valuable insight into the atomistic details of the interactions driving those specificities. Recent literature has reported highly discrepant results on the current ability of state-of-the-art atomistic molecular dynamics simulations to reproduce experimental binding free energy landscapes for transcription factors. Here, we resolve one important discrepancy by noting that in the case of alchemical free energy calculations involving base pair mutations, a common convention used in improving end point convergence of mixed potentials in fact can lead to erroneous results. The underlying cause for inaccurate double free energy difference estimates is specific to the particular implementation of the alchemical transformation protocol. Using the Gromacs simulation package, which is not affected by this issue, we obtain free energy landscapes in agreement with the experimental measurements; equivalent results are obtained for a small set of test cases with a modified version of the AMBER package. Our findings provide a consistent and optimistic outlook on the current state of prediction of protein−DNA binding free energy interactions using molecular dynamics simulations and an important precaution for appropriate end point handling in a broad range of free energy calculations.

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评论“基于分子动力学模拟的蛋白质-DNA结合自由能态势预测的不足”

序列特异性DNA结合转录因子在所有生物体的转录调控中起着至关重要的作用。因此，可靠的计算机模拟方法的发展可预测转录因子的结合亲和力格局，从而有望提供对转录因子特异性的快速筛选，同时，可对驱动这些特异性的相互作用的原子学细节产生宝贵的见解。最近的文献报道了有关最新的原子分子动力学模拟当前再现转录因子的实验性结合自由能态势的能力的高度不同的结果。在此，我们注意到一个重要的差异，即在涉及碱基对突变的炼金术自由能计算中，实际上，用于改善混合电位的端点收敛的通用约定实际上可能导致错误的结果。双自由能差估算值不准确的根本原因特定于炼金术转化规程的特定实现。使用不受此问题影响的Gromacs仿真软件包，我们获得了与实验测量结果一致的自由能态。使用AMBER软件包的修改版，可以在一小组测试用例中获得相同的结果。我们的发现为使用分子动力学模拟的蛋白质-DNA结合自由能相互作用的当前预测状态提供了一致而乐观的前景，并为在广泛的自由能计算中进行适当的终点处理提供了重要的预防措施。