Fig 1.
Enhanced sampling of base pair opening by adaptively biasing along dN1N3.
The opening of a base pair can be described either by the distance coordinate dN1N3 or by two dihedral angles θ, one for each base (A). The closed state (gray configuration) is characterized by θ ≈ 0 and small dN1N3. Open configurations (black) have larger dN1N3 values and negative or positive θ values, depending on the direction of opening. Here, we improve sampling of the opening event by applying a bias along dN1N3 using the adaptive biasing method AWH. Example trajectories are shown for one such simulation, for the case of opening of an AT base pair (B). Both θ angles are sampled simultaneously, according to their Boltzmann distribution at each given value of dN1N3. After exiting an initial stage of the method (dashed vertical line), sampling of dN1N3 is expected to be roughly uniform and its dynamics diffusive.
Fig 2.
The simulated base sequences, L and M.
Sequence differences are marked by ‘ × ’. Gray background indicate the target base pairs simulated in this study. The same sequences apart from the added end base pairs have been characterized in NMR experiments [6].
Fig 3.
Free energy profiles along the reaction coordinate dN1N3.
Continuous error bars indicate ±1σ (see S1 Appendix). Base pairs with the same nearest neighbors have the same color but either solid or dashed lines. Circles mark the distance where the imino proton is hydrogen bonded with water 20% of the time.
Fig 4.
Sampled base pair configurations.
Representative configurations at different dN1N3 values were chosen from Parmbsc1 L:AT12 (A–D) and M:CG11 trajectories (E–H). The distance values are in the figure, indicated by a dotted line. Carbon atoms are shown in gray, hydrogens in white, oxygens in red and nitrogens in blue. Waters within hydrogen bond distance of donor/acceptor atoms on both bases are also included to show examples of water bridges. Acceptor atoms that are very often in contact with Na+ in similar configurations are marked with a ’+’. Base-paired WC configurations (A), (E) are shown in line representation behind the open configurations, (B–D) and (F–H), to help visualize the extent of opening. Note that no timeline is implied from left to right.
Fig 5.
Calculated and experimental opening free energies.
Base pairs are grouped according to the nearest neighbor triplet sequence, see main text for details. Note that there is no experimental data available for certain base pairs.
Fig 6.
Local base-pair parameter histograms along dN1N3.
The data is from all Parmbsc1 simulations of base pairs L:AT12 (A) and M:CG11 (B), biased along dN1N3. The histograms have been normalized by dividing by the maximum count along each distance slice. Note that no timeline is implied from left to right.
Table 1.
Preferred opening modes.
Fig 7.
Free energy landscape of dN1N3 and the six-member ring distance.
The definitions of both coordinates are indicated in the figure.