AMBER RNA力场中氢键固定的自动学习
Automatic learning of hydrogen-bond fixes in an AMBER RNA force field
摘要：
电流力场复制RNA结构动力学的能力是有限的。已经开发了几种方法来利用实验数据，以加强与实验的协议。我们在这里扩展了现有的框架，它允许任意选择力场校正项，以配合从模拟和相应的实验计算的观测值之间的差异量化。我们应用一个强大的正则化协议，以避免过度拟合，并介绍和比较了一些不同的正则化策略，即L1-，L2-，Kish大小-，相对Kish大小-和相对熵-处罚。训练集包括GACC四聚体以及更具挑战性的系统，即gcGAGAgc和gcUUCGgc RNA四环。AMBER RNA力场中的特定分子内氢键通过自动确定的参数进行校正，我们称之为gHBfix $_{opt}$。一个验证，涉及一个单独的模拟系统中存在的训练集（gcUUCGgc）和新的系统中没有看到在训练（CAAU和UUUU四聚体）显示改进有关的天然人口的四环以及良好的协议NMR实验四聚体时，使用新的参数。然后，我们模拟折叠的RNA（扭结-转弯和L1茎rRNA），包括训练集中不充分存在的氢键类型。这允许命名为gHBfix 21的参数集的最终修改，并建议适用于更广泛的RNA系统。
英文摘要：
The capability of current force fields to reproduce RNA structural dynamics is limited. Several methods have been developed to take advantage of experimental data in order to enforce agreement with experiments. We herein extend an existing framework, which allows arbitrarily chosen force-field correction terms to be fitted by quantification of the discrepancy between observables back-calculated from simulation and corresponding experiments. We apply a robust regularization protocol to avoid overfitting, and additionally introduce and compare a number of different regularization strategies, namely L1-, L2-, Kish Size-, Relative Kish Size- and Relative Entropy-penalties. The training set includes a GACC tetramer as well as more challenging systems, namely gcGAGAgc and gcUUCGgc RNA tetraloops. Specific intramolecular hydrogen bonds in the AMBER RNA force field are corrected with automatically determined parameters that we call gHBfix$_{opt}$. A validation involving a separate simulation of a system present in the training set (gcUUCGgc) and new systems not seen during training (CAAU and UUUU tetramers) displays improvements regarding native population of the tetraloop as well as good agreement with NMR-experiments for tetramers when using the new parameters. Then we simulate folded RNAs (a kink-turn and L1 stalk rRNA) including hydrogen bond types not sufficiently present in the training set. This allows a final modification of the parameter set which is named gHBfix21 and is suggested to be applicable to a wider range of RNA systems.
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