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

ABSTRACT: Background:Cellular 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. Results:The 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. Conclusions:The 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.

SUBMITTER: Yildirim A

PROVIDER: S-EPMC6286541 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Yildirim Asli A Brenner Nathalie N Sutherland Robert R Feig Michael M

BMC biophysics 20181207

<h4>Background</h4>Cellular 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.<h4>Results</h4>The effect of protein crowding on the conformational preferences of DNA (deoxyribonucleic acid) is described from fully atomistic molecular dynamics s ...[more]

PMID: 30555686

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Project description:Large-scale analyses of protein-protein interactions based on coarse-grain molecular docking simulations and binding site predictions resulting from evolutionary sequence analysis, are possible and realizable on hundreds of proteins with variate structures and interfaces. We demonstrated this on the 168 proteins of the Mintseris Benchmark 2.0. On the one hand, we evaluated the quality of the interaction signal and the contribution of docking information compared to evolutionary information showing that the combination of the two improves partner identification. On the other hand, since protein interactions usually occur in crowded environments with several competing partners, we realized a thorough analysis of the interactions of proteins with true partners but also with non-partners to evaluate whether proteins in the environment, competing with the true partner, affect its identification. We found three populations of proteins: strongly competing, never competing, and interacting with different levels of strength. Populations and levels of strength are numerically characterized and provide a signature for the behavior of a protein in the crowded environment. We showed that partner identification, to some extent, does not depend on the competing partners present in the environment, that certain biochemical classes of proteins are intrinsically easier to analyze than others, and that small proteins are not more promiscuous than large ones. Our approach brings to light that the knowledge of the binding site can be used to reduce the high computational cost of docking simulations with no consequence in the quality of the results, demonstrating the possibility to apply coarse-grain docking to datasets made of thousands of proteins. Comparison with all available large-scale analyses aimed to partner predictions is realized. We release the complete decoys set issued by coarse-grain docking simulations of both true and false interacting partners, and their evolutionary sequence analysis leading to binding site predictions. Download site: http://www.lgm.upmc.fr/CCDMintseris/

Dataset Information

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

Publications

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

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