Examining Electrostatic Influences on Base-Flipping: A Comparison of TIP3P and GB Solvent Models

Abstract

Recently, it was demonstrated that implicit solvent models were capable of generating stable B-form DNA structures. Specifically, generalized Born (GB) implicit solvent models have improved regarding the solvation of conformational sampling of DNA [1,2]. Here, we examine the performance of the GBSW and GBMV models in CHARMM for characterizing base flipping free energy profiles of undamaged and damaged DNA bases. Umbrella sampling of the base flipping process was performed for the bases cytosine, uracil and xanthine. The umbrella sampling simulations were carried-out with both explicit (TIP3P) and implicit (GB) solvent in order to establish the impact of the solvent model on base flipping. Overall, base flipping potential of mean force (PMF) profiles generated with GB solvent resulted in a greater free energy difference of flipping than profiles generated with TIP3P. One of the significant differences between implicit and explicit solvent models is the approximation of solute-solvent interactions in implicit solvent models. We calculated electrostatic interaction energies between explicit water molecules and the base targeted for flipping. These interaction energies were calculated over the base flipping reaction coordinate to illustrate the stabilizing effect of the explicit water molecules on the flipped-out state. It is known that nucleic base pair hydrogen bonds also influenced the free energy of flipping since these favorable interactions must be broken in order for a base to flip-out of the helix. The Watson-Crick base pair hydrogen bond fractions were calculated over the umbrella sampling simulation windows in order to determine the effect of base pair interactions on the base flipping free energy. It is shown that interaction energies between the flipping base and explicit water molecules are responsible for the lower base flipping free energy difference in the explicit solvent PMF profiles.

Thermodynamics, morphology, and kinetics of early-stage self-assembly of π-conjugated oligopeptides

“…Consistent with simulations of DNA base flipping in Ref. [55], we find simulations conducted in implicit solvent greatly overestimate the free energy computed in explicit solvent, in this case by 40%.…”

“…This simple approach can be considered a form of the PMF matching approach to force field parameterisation frequently used to optimise coarse grained molecular potentials. [55,61,62] In this respect, our approach shares similarities with Boltzmann inversion (BI) wherein interaction potentials in the coarse-grained system are optimised to match distribution functions observed in all-atom simulations. [59,63] In the case of pair potentials, this reduces to matching of the pairwise PMFs.…”

Structure and Dynamics of a Fusion Peptide Helical Hairpin on the Membrane Surface: Comparison of Molecular Simulations and NMR

“…The lack of direct interactions with solvent or membrane atoms can influence thermodynamic ensembles generated from implicit models. 55 …”

Free energy landscape and transition pathways from Watson–Crick to Hoogsteen base pairing in free duplex DNA

“…Although this CPR result shed light on mechanistic aspects of bp transitions, it raised interpretative concerns due to the complete omission of an entropic contribution (- TΔS ). Furthermore, this computational approach involved the use of the implicit solvation model, which was recently shown to overestimate overall energetics for base flipping of duplex DNAs ( 18 ). Therefore, to produce more reliable pictures of the bp transition process, an all-atom level computation of free energy landscape under explicit solvation is required.…”

“…Due to its fundamental importance for understanding the intrinsic functions of duplex DNAs, base flipping has been the subject of extensive experiments ( 19 , 20 ) and computer simulations ( 18 , 21 – 26 ). In particular, previous all-atom base flipping simulations on free DNA ( 18 , 21 – 26 ) and protein/DNA complex ( 27 – 29 ) have provided much insight of this event at atomistic resolution. All these simulations emphasized purely base opening, indicating that purine base flipping has a lower free energy barrier than that of pyrimidine case and occurs more favorably in the major groove than in the minor groove.…”