Dataset Information

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation.

ABSTRACT: Topological constraints, such as those associated with DNA supercoiling, play an integral role in genomic regulation and organization in living systems. However, physical understanding of the principles that underlie DNA organization at biologically relevant length scales remains a formidable challenge. We develop a coarse-grained simulation approach for predicting equilibrium conformations of supercoiled DNA. Our methodology enables the study of supercoiled DNA molecules at greater length scales and supercoiling densities than previously explored by simulation. With this approach, we study the conformational transitions that arise due to supercoiling across the full range of supercoiling densities that are commonly explored by living systems. Simulations of ring DNA molecules with lengths at the scale of topological domains in the Escherichia coli chromosome (?10 kilobases) reveal large-scale conformational transitions elicited by supercoiling. The conformational transitions result in three supercoiling conformational regimes that are governed by a competition among chiral coils, extended plectonemes, and branched hyper-supercoils. These results capture the nonmonotonic relationship of size versus degree of supercoiling observed in experimental sedimentation studies of supercoiled DNA, and our results provide a physical explanation of the conformational transitions underlying this behavior. The length scales and supercoiling regimes investigated here coincide with those relevant to transcription-coupled remodeling of supercoiled topological domains, and we discuss possible implications of these findings in terms of the interplay between transcription and topology in bacterial chromosome organization.

SUBMITTER: Krajina BA

PROVIDER: S-EPMC5052444 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation.

Krajina Brad A BA Spakowitz Andrew J AJ

Biophysical journal 20161001 7

Topological constraints, such as those associated with DNA supercoiling, play an integral role in genomic regulation and organization in living systems. However, physical understanding of the principles that underlie DNA organization at biologically relevant length scales remains a formidable challenge. We develop a coarse-grained simulation approach for predicting equilibrium conformations of supercoiled DNA. Our methodology enables the study of supercoiled DNA molecules at greater length scale ...[more]

PMID: 27705758

Similar Datasets

Project description:Amyloid peptides are known to self-assemble into larger aggregates that are linked to the pathogenesis of many neurodegenerative disorders. In contrast to primary nucleation, recent experimental and theoretical studies have shown that many toxic oligomeric species are generated through secondary processes on a pre-existing fibrillar surface. Nucleation, for example, can also occur along the surface of a pre-existing fibril-secondary nucleation-as opposed to the primary one. However, explicit pathways are still not clear. In this study, we use molecular dynamics simulation to explore the free energy landscape of a free Abeta monomer binding to an existing fibrillar surface. We specifically look into several potential Abeta structural precursors that might precede some secondary events, including elongation and secondary nucleation. We find that the overall process of surface-dependent events can be described at least by the following three stages: 1. Free diffusion 2. Downhill guiding 3. Dock and lock. And we show that the outcome of adding a new monomer onto a pre-existing fibril is pathway-dependent, which leads to different secondary processes. To understand structural details, we have identified several monomeric amyloid precursors over the fibrillar surfaces and characterize their heterogeneity using a probability contact map analysis. Using the frustration analysis (a bioinformatics tool), we show that surface heterogeneity correlates with the energy frustration of specific local residues that form binding sites on the fibrillar structure. We further investigate the helical twisting of protofilaments of different sizes and observe a length dependence on the filament twisting. This work presents a comprehensive survey over the properties of fibril growth using a combination of several openMM-based platforms, including the GPU-enabled openAWSEM package for coarse-grained modeling, MDTraj for trajectory analysis, and pyEMMA for free energy calculation. This combined approach makes long-timescale simulation for aggregation systems as well as all-in-one analysis feasible. We show that this protocol allows us to explore fibril stability, surface binding affinity/heterogeneity, as well as fibrillar twisting. All these properties are important for understanding the molecular mechanism of surface-catalyzed secondary processes of fibril growth.

Dataset Information

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation.

Publications

Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets