Booth Jonathan, Alexandru-Crivac Christina-Nicoleta, Rickaby Kirstie A, Nneoyiegbe Ada F, Umeobika Ugochukwu, McEwan Andrew R, Trembleau Laurent, Jaspars Marcel, Houssen Wael E, Shalashilin Dmitrii V
School of Chemistry, University of Leeds , Leeds, LS2 9JT, United Kingdom.
Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen , Aberdeen AB24 3UE, Scotland, United Kingdom.
J Phys Chem Lett. 2017 May 18;8(10):2310-2315. doi: 10.1021/acs.jpclett.7b00848. Epub 2017 May 10.
An in silico computational technique for predicting peptide sequences that can be cyclized by cyanobactin macrocyclases, e.g., PatG, is reported. We demonstrate that the propensity for PatG-mediated cyclization correlates strongly with the free energy of the so-called pre-cyclization conformation (PCC), which is a fold where the cyclizing sequence C and N termini are in close proximity. This conclusion is driven by comparison of the predictions of boxed molecular dynamics (BXD) with experimental data, which have achieved an accuracy of 84%. A true blind test rather than training of the model is reported here as the in silico tool was developed before any experimental data was given, and no parameters of computations were adjusted to fit the data. The success of the blind test provides fundamental understanding of the molecular mechanism of cyclization by cyanobactin macrocyclases, suggesting that formation of PCC is the rate-determining step. PCC formation might also play a part in other processes of cyclic peptides production and on the practical side the suggested tool might become useful for finding cyclizable peptide sequences in general.
报道了一种用于预测可被蓝细菌素大环化酶（如PatG）环化的肽序列的计算机计算技术。我们证明，PatG介导的环化倾向与所谓的环化前构象（PCC）的自由能密切相关，PCC是一种环化序列的C端和N端紧密相邻的折叠结构。这一结论是通过将盒装分子动力学（BXD）的预测结果与实验数据进行比较得出的，实验数据的准确率达到了84%。这里报道的是一次真正的盲测而非模型训练，因为该计算机工具是在任何实验数据给出之前开发的，并且没有调整计算参数以拟合数据。盲测的成功为蓝细菌素大环化酶环化的分子机制提供了基本理解，表明PCC的形成是速率决定步骤。PCC的形成也可能在环肽产生的其他过程中起作用，并且从实际应用角度来看，所建议的工具可能总体上对寻找可环化的肽序列有用。
