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WIREs Comput Mol Sci
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Theoretical studies of nucleic acids folding

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Abstract The mechanism of how RNA and DNA molecules fold into defined three‐dimensional (3D) structures is still not well understood. Molecular simulation approaches are increasingly being used to study structure formation processes of nucleic acids and to understand the driving forces for folding. It is possible to use molecular dynamics (MD) simulations based on a classical force field to follow the dynamics of nucleic acids at atomic resolution and high time resolution and including surrounding solvent molecules and ions explicitly. Recent studies indicate that it is possible to investigate folding of small motifs such as hairpin structures using MD simulations. However, this approach is still limited by the currently accessible time scales and force field accuracy. Advanced sampling methods such as the replica‐exchange MD (REMD) approach allow significant enhancement of conformational sampling of nucleic acids and could help to systematically study structure formation processes and to refine force fields. In case of large RNAs or RNA containing macromolecular structures, coarse‐grained representations can help to overcome current computational limitations. In combination with experimentally derived constraints and predicted secondary structure, several approaches have been developed to fold RNA molecules into possible 3D structures. Such structural model can often be helpful to plan experiments or to interpret experimental results. This article is categorized under: Electronic Structure Theory > Density Functional Theory

Folding of RNA molecules based on a coarse‐grained representation and experimental or bioinformatics data possibly included as restraints during an MD or MC simulation. The ensemble of possible solutions compatible with experimental data are often finally refined using an atomistic description of the RNA molecules.

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Example of a T‐REMD simulation on a DNA‐hairpin structure (sequence: dGCGCAGC) starting from an extended single‐stranded start structure (see Ref 65). The root‐mean‐square deviation (RMSD) of the simulated conformations from the experimentally known hairpin structure versus simulation time is plotted for a regular continuous MD simulation (upper graph on the left panel) and compared to the REMD simulation (lower graph on the left panel, result for sampling in the lowest temperature replica). The REMD simulation rapidly exchanges conformations that include the known folded state as dominant conformation (low RMSD) but also alternative conformations (snapshots shown in the right panel).

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Schematic representation of the replica‐exchange MD simulation methodology. Several simulations of noninteracting copies of the nucleic acid system (replicas) are performed in parallel. The replicas differ in temperature of force field (Hamiltonian). At frequent intervals exchanges between neighboring replicas are attempted and accepted or rejected according to a Metropolis criterion.

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Electronic Structure Theory > Density Functional Theory

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