Local and global effects of strong DNA bending induced during molecular dynamics simulations

Abstract

DNA bending plays an important role in many biological processes, but its molecular and energetic details as a function of base sequence remain to be fully understood. Using a recently developed restraint, we have studied the controlled bending of four different B-DNA oligomers using molecular dynamics simulations. Umbrella sampling with the AMBER program and the recent parmbsc0 force field yield free energy curves for bending. Bending 15-base pair oligomers by 90° requires roughly 5 kcal mol−1, while reaching 150° requires of the order of 12 kcal mol−1. Moderate bending occurs mainly through coupled base pair step rolls. Strong bending generally leads to local kinks. The kinks we observe all involve two consecutive base pair steps, with disruption of the central base pair (termed Type II kinks in earlier work). A detailed analysis of each oligomer shows that the free energy of bending only varies quadratically with the bending angle for moderate bending. Beyond this point, in agreement with recent experiments, the variation becomes linear. An harmonic analysis of each base step yields force constants that not only vary with sequence, but also with the degree of bending. Both these observations suggest that DNA is mechanically more complex than simple elastic rod models would imply.

Recent progress on the mechanics of sharply bent DNA

“…Importantly, the nick-dependent flexible defect excitation has a sensitive dependence on temperature, which is significantly suppressed when the temperature is reduced from 300 K to 290 K [46]. These and previous simulations performed for sharply bent, nick-free DNA also revealed that excitation of flexible defects involves basepair disruptions [45,46,53], which result in local kinks around the defects. However, excitation of flexible defects inside nick-free DNA is much less favorable than those at nicked sites.…”

“…Among these possible defects, both a locally melted DNA basepairs [45,46] and an intrinsically kinked DNA basepair step [45,47] have been observed in molecular dynamics (MD) simulations of sharply bent DNA molecules.…”

Intermolecular Hydrogen Bonding and Vibrational Analysis of N,N-Dimethylformamide Hexamer Cluster

“…Further, it has much heavier than small molecules. Recent study 33 of 15-base pair oligomer of single stranded nucleic acid fragments showed that the bending by 90º requires roughly 5 kcal mol -1 where the effective bending force constants of 0.02 ~ 0.06 kcal mol -1 degree -2 was reported. This corresponds to roughly 0.46 ~ 1.4 mdynÅ which is yet very huge in fact.…”

Coupled binding–bending–folding: The complex conformational dynamics of protein-DNA binding studied by atomistic molecular dynamics simulations

“…The importance of kinks for strong DNA bending was predicted by Crick and Klug [90], and kinks or internal bubbles due to local DNA melting (that is, the loss of base pairing) will increase the cyclization rate [91,92]. Type II kinks were observed in free energy simulations that used a global screw-axis coordinate to bend DNA [93]. A change in the free energy cost of bending from the quadratic to the linear regime was observed at high bending angles, where type II kinks were prevalent.…”