Atomistic insight into the kinetic pathways for Watson–Crick to Hoogsteen transitions in DNA

Abstract

DNA predominantly contains Watson–Crick (WC) base pairs, but a non-negligible fraction of base pairs are in the Hoogsteen (HG) hydrogen bonding motif at any time. In HG, the purine is rotated ∼180° relative to the WC motif. The transitions between WC and HG may play a role in recognition and replication, but are difficult to investigate experimentally because they occur quickly, but only rarely. To gain insight into the mechanisms for this process, we performed transition path sampling simulations on a model nucleotide sequence in which an AT pair changes from WC to HG. This transition can occur in two ways, both starting with loss of hydrogen bonds in the base pair, followed by rotation around the glycosidic bond. In one route the adenine base converts from WC to HG geometry while remaining entirely within the double helix. The other route involves the adenine leaving the confines of the double helix and interacting with water. Our results indicate that this outside route is more probable. We used transition interface sampling to compute rate constants and relative free energies for the transitions between WC and HG. Our results agree with experiments, and provide highly detailed insights into the mechanisms of this important process.

Discovering Collective Variables of Molecular Transitions via Genetic Algorithms and Neural Networks

“…dWC and dHG are closely related (0.64 and −0.56) to atan_dWCdHG, which is to be expected given the function’s arguments. Moreover, in ref ( 56 ), atan_dWCdHG was successfully used as a reaction coordinate to extract a rate constants of the transition, which confirms its validity as an important CV. For a full overview of all the pairwise correlations, see SI Figure 2 .…”

“…We start from two 100 ns unbiased pre-equilibrated MD simulations, one sampling the WC state and the other sampling the HG state of the DNA segment. The simulation parameters are the same as in ref ( 56 ). From these trajectories, frames with an interval of 10 ps were taken and used as input for the framework.…”

“…The B-DNA sequence is modeled with the BSC1 force field. 60 Further details regarding the simulation can be obtained from ref ( 56 ).…”

“… 59 To observe the effects in the competition, we introduce yet another somewhat redundant CV; tBFs is a simplified version of tBF, which does not use centers of mass and is likely less reliable in the face of local deformations. dWC, dHG, dHB, and atan_dWCdHG were used in ref ( 56 ) to perform and analyze WC-to-HG path sampling simulations. tGBs, dCC, dHG, aBPT, and tBP1P2T are based on ref ( 63 ), where they were used to identify HG base pairs in a survey of X-ray structures.…”

Transition Path Sampling as Markov Chain Monte Carlo of Trajectories: Recent Algorithms, Software, Applications, and Future Outlook

“…Related to enzymes are molecular configurational changes in proteins, [60,62,[132][133][134] (including protein dissociation [68] ), lipids, [135] DNA, [136][137][138][139][140][141] and even transport across ion channels. [142] Here, the challenge is that paths tend to be more diffusive, and thus longer (order 1-10 ns), and states are more difficult to define.…”