Department of Medicinal Chemistry, College of Pharmacy, University of Utah, 2000 East 30 South Skaggs 306, Salt Lake City, Utah 84112, United States.
J Chem Theory Comput. 2023 Apr 25;19(8):2198-2212. doi: 10.1021/acs.jctc.3c00130. Epub 2023 Mar 28.
Flexible nucleic acid structures can be challenging to accurately resolve with currently available experimental structural determination techniques. As an alternative, molecular dynamics (MD) simulations can provide a window into understanding the unique dynamics and population distributions of these biomolecules. Previously, molecular dynamics simulations of noncanonical (non-duplex) nucleic acids have proven difficult to accurately model. With a new influx of improved nucleic acid force fields, achieving an in-depth understanding of the dynamics of flexible nucleic acid structures may be achievable. In this project, currently available nucleic acid force fields are evaluated using a flexible yet stable model system: the DNA mini-dumbbell. Prior to MD simulations, nuclear magnetic resonance (NMR) re-refinement was accomplished using improved refinement techniques in explicit solvent to yield DNA mini-dumbbell structures with better agreement between the newly determined PDB snapshots, with the NMR data itself, as well as the unrestrained simulation data. Starting from newly determined structures, a total aggregate of over 800 μs of production data between 2 DNA mini-dumbbell sequences and 8 force fields was collected to compare to these newly refined structures. The force fields tested spanned from traditional Amber force fields: bsc0, bsc1, OL15, and OL21 to Charmm force fields: Charmm36 and the Drude polarizable force field, as well as force fields from independent developers: Tumuc1 and CuFix/NBFix. The results indicated slight variations not only between the different force fields but also between the sequences as well. Given our previous experiences with high populations of potentially anomalous structures in RNA UUCG tetraloops and in various tetranucleotides, we expected the mini-dumbbell system to be challenging to accurately model. Surprisingly, many of the recently developed force fields generated structures in good agreement with experiments. Yet, each of the force fields provided a different distribution of potentially anomalous structures.
具有柔性的核酸结构很难通过现有的实验结构确定技术进行精确解析。作为替代方法，分子动力学 (MD) 模拟可以提供一个窗口，帮助理解这些生物分子的独特动力学和种群分布。以前，对非规范（非双链）核酸的分子动力学模拟很难进行准确建模。随着新的改进的核酸力场的出现，深入了解柔性核酸结构的动力学特性可能成为现实。在这个项目中，使用灵活且稳定的模型系统——DNA 迷你哑铃，评估了当前可用的核酸力场。在进行 MD 模拟之前，使用改进的显式溶剂中的重新细化技术完成了核磁共振 (NMR) 再细化，以产生 DNA 迷你哑铃结构，这些结构在新确定的 PDB 快照之间、与 NMR 数据本身以及无约束模拟数据之间具有更好的一致性。从新确定的结构开始，在 2 个 DNA 迷你哑铃序列和 8 个力场之间总共收集了超过 800 μs 的生产数据，以与这些新细化的结构进行比较。测试的力场涵盖了从传统的 Amber 力场：bsc0、bsc1、OL15 和 OL21 到 Charmm 力场：Charmm36 和 Drude 极化力场，以及来自独立开发者的力场：Tumuc1 和 CuFix/NBFix。结果表明，不仅不同力场之间存在细微差异，而且序列之间也存在细微差异。考虑到我们之前在 RNA UUCG 四联体和各种四核苷酸中存在高比例潜在异常结构的经验，我们预计迷你哑铃系统难以进行准确建模。令人惊讶的是，许多最近开发的力场生成的结构与实验结果非常吻合。然而，每个力场都提供了不同的潜在异常结构分布。
