Zgarbová Marie, Jurečka Petr, Lankaš Filip, Cheatham Thomas E, Šponer Jiří, Otyepka Michal
Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University , 17 listopadu 12, 77146 Olomouc, Czech Republic.
Laboratory of Informatics and Chemistry, University of Chemistry and Technology Prague , Technická 5, 16628 Prague, Czech Republic.
J Chem Inf Model. 2017 Feb 27;57(2):275-287. doi: 10.1021/acs.jcim.6b00621. Epub 2017 Jan 20.
Reliable representation of the B-DNA base-pair step twist is one of the crucial requirements for theoretical modeling of DNA supercoiling and other biologically relevant phenomena in B-DNA. It has long been suspected that the twist is inaccurately described by current empirical force fields. Unfortunately, comparison of simulation results with experiments is not straightforward because of the presence of BII backbone substates, whose populations may differ in experimental and simulation ensembles. In this work, we provide a comprehensive view of the effect of BII substates on the overall B-DNA helix twist and show how to reliably compare twist values from experiment and simulation in two scenarios. First, for longer DNA segments freely moving in solution, we show that sequence-averaged twists of different BI/BII ensembles can be compared directly because of approximate cancellation of the opposing BII effects. Second, for sequence-specific data, such as a particular base-pair step or tetranucleotide twist, can be compared only for a clearly defined BI/BII backbone conformation. For the purpose of force field testing, we designed a compact set of fourteen 22-base-pair B-DNA duplexes (Set 14) containing all 136 distinct tetranucleotide sequences and carried out a total of 84 μs of molecular dynamics simulations, primarily with the OL15 force field. Our results show that the ff99bsc0εζχ, parmbsc1, and OL15 force fields model the B-DNA helical twist in good agreement with X-ray and minicircle ligation experiments. The comprehensive understanding obtained regarding the effect of BII substates on the base-pair step geometry should aid meaningful comparisons of various conformational ensembles in future research.
对B-DNA碱基对步移扭转进行可靠表征是DNA超螺旋及其他与B-DNA生物学相关现象的理论建模的关键要求之一。长期以来，人们一直怀疑当前的经验力场对扭转的描述不准确。不幸的是，由于存在BII主链亚态，模拟结果与实验的比较并不直接，其在实验和模拟系综中的丰度可能不同。在这项工作中，我们全面阐述了BII亚态对整体B-DNA螺旋扭转的影响，并展示了在两种情况下如何可靠地比较实验和模拟中的扭转值。首先，对于在溶液中自由移动的较长DNA片段，我们表明不同BI/BII系综的序列平均扭转可以直接比较，因为相反的BII效应近似抵消。其次，对于序列特异性数据，例如特定的碱基对步移或四核苷酸扭转，只有在明确界定的BI/BII主链构象下才能进行比较。为了进行力场测试，我们设计了一组紧凑的14个22碱基对的B-DNA双链体（Set 14），包含所有136个不同的四核苷酸序列，并主要使用OL15力场进行了总共84微秒的分子动力学模拟。我们的结果表明，ff99bsc0εζχ、parmbsc1和OL15力场对B-DNA螺旋扭转的建模与X射线和小环连接实验结果吻合良好。关于BII亚态对碱基对步移几何结构影响的全面理解，应有助于未来研究中对各种构象系综进行有意义的比较。
