Alchemical Free-Energy Calculations of Watson–Crick and Hoogsteen Base Pairing Interconversion in DNA

Abstract

Hoogsteen (HG) base pairs have a transient nature and can be structurally similar to Watson−Crick (WC) base pairs, making their occurrence and thermodynamic stability difficult to determine experimentally. Herein, we employed the restrain−freeenergy perturbation−release (R-FEP-R) method to calculate the relative free energy of the WC and HG base pairing modes in isolated and bound DNA systems and predict the glycosyl torsion conformational preference of purine bases. Notably, this method does not require prior knowledge of the transition pathway between the two end states. Remarkably, relatively fast convergence was reached, with results in excellent agreement with experimental data for all the examined DNA systems. The R-REP-R method successfully determined the stability of HG base pairing and more generally, the conformational preference of purine bases, in these systems. Therefore, this computational approach can help to understand the dynamic equilibrium between the WC and HG base pairing modes in DNA.

Deciphering the Role of Anions of Ionic Liquids in Modulating the Structure and Stability of ct-DNA in Aqueous Solutions

“…We have considered the G5–C20 in the ct -DNA that shows significant stability with respect to the relative fluctuations. These hydrogen bonding distances are of interest in studying the stability and conformational dynamics of DNA. , The distances are mostly conserved in the base pairs, and the glycosylic dihedral shows negligible change. This shows the stability of the ct -DNA in the IL medium.…”

“…The binding modes of the anions with the DNA groove is also observed from the simulation trajectories. Yet, further studies need to be performed taking longer simulation time and using different force-fields, or employing advanced sampling methods to obtain the complete information. − …”

Elucidating the Molecular Determinants of the Binding Modes of a Third-Generation HIV-1 Integrase Strand Transfer Inhibitor: The Importance of Side Chain and Solvent Reorganization

“…In contrast to enhanced sampling methods that use pre-defined physical reaction coordinates to connect two conformational basins, the R-FEP-R method (restrain–free energy perturbation–release) [ 16 ] uses a dual topology alchemical pathway to circumvent the high free energy barriers that may arise from both intramolecular and intermolecular interactions in a crowded environment. R-FEP-R has been successfully applied to compute the free energy of conformational changes in protein loops [ 16 ] and DNA base pairing [ 17 ]. Here, we apply this method to estimate the conformational free energy difference between the two binding modes of the INSTI 4f in complexes with either HIV-1 or PFV intasomes.…”

Unveiling the Intermolecular Interactions between Drug 5-Fluorouracil and Watson–Crick/Hoogsteen Base Pairs: A Computational Analysis

“…Wang and co-workers investigated the infrared spectroscopy and nuclear-vibrating patterns of multiple H-bonds in WC DNA base pairs using DFT calculations and observed the existence of H-bond cooperativity in them . The interconversion of HT to WC conversion was studied using the restrain-free-energy perturbation-release method, in which HT base pairing was more stable by 2.25 kcal mol –1 than the anticonformation . The interaction of hydroxyurea and 5FU with WC base pairs was studied using DFT methods .…”