The transition mechanism of DNA overstretching: a microscopic view using molecular dynamics

Abstract

The overstretching transition in torsionally unconstrained DNA is studied by means of atomistic molecular dynamics simulations. The free-energy profile as a function of the length of the molecule is determined through the umbrella sampling technique providing both a thermodynamic and a structural characterization of the transition pathway. The zero-force free-energy profile is monotonic but, in accordance with recent experimental evidence, becomes two-state at high forces. A number of experimental results are satisfactorily predicted: (i) the entropic and enthalpic contributions to the free-energy difference between the basic (B) state and the extended (S) state; (ii) the longitudinal extension of the transition state and (iii) the enthalpic contribution to the transition barrier. A structural explanation of the experimental finding that overstretching is a cooperative reaction characterized by elementary units of approximately 22 base pairs is found in the average distance between adenine/thymine-rich regions along the molecule. The overstretched DNA adopts a highly dynamical and structurally disordered double-stranded conformation which is characterized by residual base pairing, formation of non-native intra-strand hydrogen bonds and effective hydrophobic screening of apolar regions.

Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics

“…This limitation results in the incapability of understanding why dsDNA twiststretch coupling changes with an applied force (2,3,32,33). An alternative approach computes potential(s) of mean force (PMF) (26,29,34). Nevertheless, obtaining a PMF where a given reaction coordinate (e.g., elongation, twist) is sampled enough to ensure thermal equilibrium is reached at each point is a very demanding computational task.…”

Equilibrium and Kinetics of DNA Overstretching Modeled with a Quartic Energy Landscape

“…Bianco et al (31) and Bongini et al (32) studied the transition kinetics of the overstretching transition using force-steps in pulling experiments of l-DNA (~48.5 kbp), where they found that the cooperative length of the B-to-S transition is~22-25 bp. The experimental findings of Bianco et al (31) and Bongini et al (32) have been recently satisfactorily reproduced using atomistic molecular-dynamics simulations (24).…”

“…Regardless of temperature T, length L, or ionic concentration I, for experimental curves where the change in extension is Lz 1:7 L the cooperativity of the system is given approximately by l˛ [22][23][24][25]bp. Although T, I, and L are different among the data sets presented in Fig.…”

“…The initial steered molecular-dynamic simulations used to study the DNA overstretching phenomena (22)(23)(24) gave transition forces one order-of-magnitude larger than the experimental ones. Simulations in which the free-energy profile of the system was determined using an umbrella sampling technique have recently provided a more realistic picture of the overstretching transition (24).…”

“…Finally, with the objective of providing a deeper structural explanation at the microscopic level, DNA overstretching phenomena have also been studied using atomistic modeling (18), by means of molecular-modeling treatments with implicit solvent representations (19)(20)(21) and by using molecular-dynamic simulations (21)(22)(23). The initial steered molecular-dynamic simulations used to study the DNA overstretching phenomena (22)(23)(24) gave transition forces one order-of-magnitude larger than the experimental ones. Simulations in which the free-energy profile of the system was determined using an umbrella sampling technique have recently provided a more realistic picture of the overstretching transition (24).…”