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Elbow flexibility of the kt38 RNA kink-turn motif investigated by free-energy molecular dynamics simulations.

ABSTRACT: Kink-turns (K-turns) are common structural motifs that can introduce sharp kinks into double-stranded RNA, and have been proposed to mediate large-scale motions in the ribosome. K-turns consist of a bulge loop region flanked by trans sugar-Hoogsteen G:A pairs, and the sharp kink conformation is stabilized by A-minor interactions (adenine contacting a G:C basepair in the minor groove). Umbrella-sampling molecular dynamics simulations were used to disrupt an A-minor interaction in the ribosomal kt38 turn and to calculate the associated free-energy change. Coupling of umbrella sampling with replica exchanges between neighboring umbrella-sampling intervals could further improve the convergence of the free-energy calculations. The simulations revealed a coupled A-minor disruption and global opening of the K-turn motif, and allowed us to characterize several intermediate A-minor conformations. The calculated free-energy profile indicated a meta-stable, semi-open structure of slightly higher free energy ( approximately 1 kcal mol(-1)), separated by a small free-energy barrier ( approximately 1.5 kcal mol(-1)) from the closed (highly kinked) form. Both K-turn states are stabilized by distinct variants of the A-minor interaction. Further opening of the K-turn structure required significantly larger free-energy changes. The semi-open form had a reduced kink angle compatible with experimental data on K-turn solution structures, and opening was coupled to a continuous global unwinding of the K-turn motif. The range of free-energy changes associated with kt38 opening and unwinding are compatible with the idea that K-turns may facilitate biologically relevant motions during large-scale ribosome dynamics.

SUBMITTER: Curuksu J

PROVIDER: S-EPMC2756366 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Elbow flexibility of the kt38 RNA kink-turn motif investigated by free-energy molecular dynamics simulations.

Curuksu Jeremy J Sponer Jiri J Zacharias Martin M

Biophysical journal 20091001 7

Kink-turns (K-turns) are common structural motifs that can introduce sharp kinks into double-stranded RNA, and have been proposed to mediate large-scale motions in the ribosome. K-turns consist of a bulge loop region flanked by trans sugar-Hoogsteen G:A pairs, and the sharp kink conformation is stabilized by A-minor interactions (adenine contacting a G:C basepair in the minor groove). Umbrella-sampling molecular dynamics simulations were used to disrupt an A-minor interaction in the ribosomal kt ...[more]

PMID: 19804732

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Project description:The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on" and "off." Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of the FEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from approximately 25,000 to 2500. The computations are very efficient and the statistical error is small ( approximately 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within approximately 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.

Dataset Information

Elbow flexibility of the kt38 RNA kink-turn motif investigated by free-energy molecular dynamics simulations.

Publications

Elbow flexibility of the kt38 RNA kink-turn motif investigated by free-energy molecular dynamics simulations.

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