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Molecular Mechanics Investigation of an Adenine-Adenine Non-Canonical Pair Conformational Change.

ABSTRACT: Conformational changes are important in RNA for binding and catalysis and understanding these changes is important for understanding how RNA functions. Computational techniques using all-atom molecular models can be used to characterize conformational changes in RNA. These techniques are applied to an RNA conformational change involving a single base pair within a nine base pair RNA duplex. The Adenine-Adenine (AA) non-canonical pair in the sequence 5'GGUGAAGGCU3' paired with 3'PCCGAAGCCG5', where P is Purine, undergoes conformational exchange between two conformations on the timescale of tens of microseconds, as demonstrated in a previous NMR solution structure [Chen, G., et al., Biochemistry, 2006. 45: 6889-903]. The more populated, major, conformation was estimated to be 0.5 to 1.3 kcal/mol more stable at 30 °C than the less populated, minor, conformation. Both conformations are trans-Hoogsteen/sugar edge pairs, where the interacting edges on the adenines change with the conformational change. Targeted Molecular Dynamics (TMD) and Nudged Elastic Band (NEB) were used to model the pathway between the major and minor conformations using the AMBER software package. The adenines were predicted to change conformation via intermediates in which they are stacked as opposed to hydrogen-bonded. The predicted pathways can be described by an improper dihedral angle reaction coordinate. Umbrella sampling along the reaction coordinate was performed to model the free energy profile for the conformational change using a total of 1800 ns of sampling. Although the barrier height between the major and minor conformations was reasonable, the free energy difference between the major and minor conformations was the opposite of that expected based on the NMR experiments. Variations in the force field applied did not improve the misrepresentation of the free energies of the major and minor conformations. As an alternative, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approximation was applied to predict free energy differences between the two conformations using a total of 800 ns of sampling. MM-PBSA also incorrectly predicted the major conformation to be higher in free energy than the minor conformation.

SUBMITTER: Van Nostrand KP

PROVIDER: S-EPMC3221466 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Molecular Mechanics Investigation of an Adenine-Adenine Non-Canonical Pair Conformational Change.

Van Nostrand Keith P KP Kennedy Scott D SD Turner Douglas H DH Mathews David H DH

Journal of chemical theory and computation 20111101 11

Conformational changes are important in RNA for binding and catalysis and understanding these changes is important for understanding how RNA functions. Computational techniques using all-atom molecular models can be used to characterize conformational changes in RNA. These techniques are applied to an RNA conformational change involving a single base pair within a nine base pair RNA duplex. The Adenine-Adenine (AA) non-canonical pair in the sequence 5'GGUGAAGGCU3' paired with 3'PCCGAAGCCG5', whe ...[more]

PMID: 22116780

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Project description:Structure and dynamics are both critical to RNA's vital functions in biology. Numerous techniques can elucidate the structural dynamics of RNA, but computational approaches based on experimental data arguably hold the promise of providing the most detail. In this Account, we highlight areas wherein molecular dynamics (MD) and quantum mechanical (QM) techniques are applied to RNA, particularly in relation to complementary experimental studies. We have expanded on atomic-resolution crystal structures of RNAs in functionally relevant states by applying explicit solvent MD simulations to explore their dynamics and conformational changes on the submicrosecond time scale. MD relies on simplified atomistic, pairwise additive interaction potentials (force fields). Because of limited sampling, due to the finite accessible simulation time scale and the approximated force field, high-quality starting structures are required. Despite their imperfection, we find that currently available force fields empower MD to provide meaningful and predictive information on RNA dynamics around a crystallographically defined energy minimum. The performance of force fields can be estimated by precise QM calculations on small model systems. Such calculations agree reasonably well with the Cornell et al. AMBER force field, particularly for stacking and hydrogen-bonding interactions. A final verification of any force field is accomplished by simulations of complex nucleic acid structures. The performance of the Cornell et al. AMBER force field generally corresponds well with and augments experimental data, but one notable exception could be the capping loops of double-helical stems. In addition, the performance of pairwise additive force fields is obviously unsatisfactory for inclusion of divalent cations, because their interactions lead to major polarization and charge-transfer effects neglected by the force field. Neglect of polarization also limits, albeit to a lesser extent, the description accuracy of other contributions, such as interactions with monovalent ions, conformational flexibility of the anionic sugar-phosphate backbone, hydrogen bonding, and solute polarization by solvent. Still, despite limitations, MD simulations are a valid tool for analyzing the structural dynamics of existing experimental structures. Careful analysis of MD simulations can identify problematic aspects of an experimental RNA structure, unveil structural characteristics masked by experimental constraints, reveal functionally significant stochastic fluctuations, evaluate the structural role of base ionization, and predict structurally and potentially functionally important details of the solvent behavior, including the presence of tightly bound water molecules. Moreover, combining classical MD simulations with QM calculations in hybrid QM/MM approaches helps in the assessment of the plausibility of chemical mechanisms of catalytic RNAs (ribozymes). In contrast, the reliable prediction of structure from sequence information is beyond the applicability of MD tools. The ultimate utility of computational studies in understanding RNA function thus requires that the results are neither blindly accepted nor flatly rejected, but rather considered in the context of all available experimental data, with great care given to assessing limitations through the available starting structures, force field approximations, and sampling limitations. The examples given in this Account showcase how the judicious use of basic MD simulations has already served as a powerful tool to help evaluate the role of structural dynamics in biological function of RNA.

Dataset Information

Molecular Mechanics Investigation of an Adenine-Adenine Non-Canonical Pair Conformational Change.

Publications

Molecular Mechanics Investigation of an Adenine-Adenine Non-Canonical Pair Conformational Change.

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