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 ff99bsc0εζOL1χOL4, 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.

Department of Medicinal Chemistry University of Utah 30 South 2000 East Skaggs 105 Salt Lake City Utah 84112 United States

Laboratory of Informatics and Chemistry University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University 17 listopadu 12 77146 Olomouc Czech Republic

Regional Centre of Advanced Technologies and Materials Department of Physical Chemistry Faculty of Science Palacky University 17 listopadu 12 77146 Olomouc Czech Republic Institute of Biophysics Academy of Sciences of the Czech Republic Královopolská 135 61265 Brno Czech Republic

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