Computational Biochemistry and Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra , Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.
J Chem Theory Comput. 2011 Jun 14;7(6):1943-50. doi: 10.1021/ct100707s. Epub 2011 May 6.
Steered molecular dynamics (SMD) simulations for the calculation of free energies are well suited for high-throughput molecular simulations on a distributed infrastructure due to the simplicity of the setup and parallel granularity of the runs. However, so far, the computational cost limited the estimation of the free energy typically over just a few pullings, thus impeding the evaluation of statistical uncertainties involved. In this work, we performed two thousand pulls for the permeation of a potassium ion in the gramicidin A pore by all-atom molecular dynamics in order to assess the bidirectional SMD protocol with a proper amount of sampling. The estimated free energy profile still shows a statistical error of several kcal/mol, while the work distributions are estimated to be non-Gaussian at pulling speeds of 10 Å/ns. We discuss the methodology and the confidence intervals in relation to increasing amounts of computed trajectories and how different permeation pathways for the potassium ion, knock-on and sideways, affect the sampling and the free energy estimation.
定向分子动力学（SMD）模拟非常适合在分布式基础设施上进行高通量分子模拟，因为其设置简单且运行具有并行粒度。然而，到目前为止，计算成本限制了自由能的估计，通常仅对几个拉动进行估计，从而阻碍了对所涉及的统计不确定性的评估。在这项工作中，我们通过全原子分子动力学对穿过革兰氏菌素 A 孔的钾离子进行了两千次拉动，以评估具有适当采样量的双向 SMD 协议。估计的自由能曲线仍然显示出几个千卡/摩尔的统计误差，而在 10 Å/ns 的拉动速度下，工作分布被估计为非高斯分布。我们讨论了与计算轨迹数量增加相关的方法和置信区间，以及钾离子的不同渗透途径（敲门和侧向）如何影响采样和自由能估计。
