Abstract
The accurate prediction of the structure and dynamics of DNA remains a major challenge in computational biology due to the dearth of precise experimental information on DNA free in solution and limitations in the DNA force-fields underpinning the simulations. A new generation of force-fields has been developed to better represent the sequence-dependent B-DNA intrinsic mechanics, in particular with respect to the BI ↔ BII backbone equilibrium, which is essential to understand the B-DNA properties. Here, the performance of MD simulations with the newly updated force-fields Parmbsc0εζOLI and CHARMM36 was tested against a large ensemble of recent NMR data collected on four DNA dodecamers involved in nucleosome positioning. We find impressive progress towards a coherent, realistic representation of B-DNA in solution, despite residual shortcomings. This improved representation allows new and deeper interpretation of the experimental observables, including regarding the behavior of facing phosphate groups in complementary dinucleotides, and their modulation by the sequence. It also provides the opportunity to extensively revisit and refine the coupling between backbone states and inter base pair parameters, which emerges as a common theme across all the complementary dinucleotides. In sum, the global agreement between simulations and experiment reveals new aspects of intrinsic DNA mechanics, a key component of DNA-protein recognition.
Highlights
Binding of DNA to proteins or small molecules is modulated by subtle sequence-dependent variations inherent to the structure and dynamics of free DNA, which facilitate or disfavor the structural fit with cognate partners [1,2,3,4]
The ability to simulate computationally the structure and dynamics of biomolecules is a major goal of structural biology
We find that the conformational states of the two facing phosphate groups of any complementary dinucleotide are not correlated in either Parmbsc0εzOLI or CHARMM36 simulations
Summary
Binding of DNA to proteins or small molecules is modulated by subtle sequence-dependent variations inherent to the structure and dynamics of free DNA, which facilitate or disfavor the structural fit with cognate partners [1,2,3,4]. MD simulations are only as reliable as the underlying energy model, typically treated with a classical force-field. Development of forcefields is complex, requires extensive efforts, and needs precise reference experimental data [7]. This latter requirement has been a complicating factor for DNA, given the paucity of reliable experimental data reflecting the fine structural details of DNA in solution [8,9,10]. Force-field shortcomings regarding the DNA backbone were addressed, including via QM studies on model compounds [11,12,13], motivated by the realization that the backbone is an essential component of the intrinsic mechanical couplings in DNA
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