Role of protein interactions in stabilizing canonical DNA features in simulations of DNA in crowded environments

Robert Sutherland,Nathalie Brenner,Asli Yildirim,Michael Feig

doi:10.1186/s13628-018-0048-y

Robert Sutherland, Nathalie Brenner + Show 2 more

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https://doi.org/10.1186/s13628-018-0048-y

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Abstract

BackgroundCellular environments are highly crowded with biological macromolecules resulting in frequent non-specific interactions. While the effect of such crowding on protein structure and dynamics has been studied extensively, very little is known how cellular crowding affects the conformational sampling of nucleic acids.ResultsThe effect of protein crowding on the conformational preferences of DNA (deoxyribonucleic acid) is described from fully atomistic molecular dynamics simulations of systems containing a DNA dodecamer surrounded by protein crowders. From the simulations, it was found that DNA structures prefer to stay in B-like conformations in the presence of the crowders. The preference for B-like conformations results from non-specific interactions of crowder proteins with the DNA sugar-phosphate backbone. Moreover, the simulations suggest that the crowder interactions narrow the conformational sampling to canonical regions of the conformational space.ConclusionsThe overall conclusion is that crowding effects may stabilize the canonical features of DNA that are most important for biological function. The results are complementary to a previous study of DNA in reduced dielectric environments where reduced dielectric environments alone led to a conformational shift towards A-DNA. Such a shift was not observed here suggested that the reduced dielectric response of cellular environments is counteracted by non-specific interactions with protein crowders under in vivo conditions.

Highlights

Biological cells are highly crowded environments due to the presence of various macromolecules
[10] and simulations [11]: (1) the volume exclusion effect has been suggested to favor more compact conformations based on entropic arguments, thereby generally stabilizing more compact states [12, 13]; (2) non-specific interactions between biomolecules and surrounding protein crowders have led to the destabilization of native states [14,15,16] as well as reduced diffusion [17]; and (3) altered solvation properties including reduced dynamic and dielectric properties [18] have implied a reduced hydrophobic effect [19, 20]
We find a general tendency of the Deoxyribonucleic acid (DNA) to favor the B-form in crowded environments, which is in contrast to the shift towards A-form DNA observed in the simpler reduced dielectric environments [20]

Summary

Introduction

Biological cells are highly crowded environments due to the presence of various macromolecules. A typical biological cell has a concentration of biomolecules in the range of 300–400 mg/ml [2], corresponding to a macromolecular volume fraction of 20–30% [3] Such an environment is substantially different from dilute solutions, the frequently considered environment in most biological experiments. Three essential crowding effects have been reported from experiments [10] and simulations [11]: (1) the volume exclusion effect has been suggested to favor more compact conformations based on entropic arguments, thereby generally stabilizing more compact states [12, 13]; (2) non-specific interactions between biomolecules and surrounding protein crowders have led to the destabilization of native states [14,15,16] as well as reduced diffusion [17]; and (3) altered solvation properties including reduced dynamic and dielectric properties [18] have implied a reduced hydrophobic effect [19, 20]. While the effect of such crowding on protein structure and dynamics has been studied extensively, very little is known how cellular crowding affects the conformational sampling of nucleic acids

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