Modeling One‐ and Two‐Photon Excitation of 4′‐(Hydroxymethyl)‐4,5′,8‐trimethylpsoralen in Complex with DNA: Solving Electron Spill‐Out Problems in Polarizable QM/MM Calculations

Abstract

The polarizable embedding (PE) method is a fully self‐consistent fragment‐based QM/MM approach that uses advanced polarizable force fields and can be applied for various environments, including solvents and DNA. However, lack of proper electronic description of the MM environment can result in electron density leakage from the QM to the MM region, an effect known as electron spill‐out (ESO). ESO can be avoided by applying effective core potentials (ECPs) on MM atoms in PE (PE‐ECP) or by including repulsion operators to model the orthogonality between the two regions, as in the polarizable density embedding (PDE) approach. In this study, the one‐ and two‐photon absorptions of 4′‐(hydroxymethyl)‐4,5′,8‐trimethylpsoralen in complex with DNA and in aqueous solution are investigated. The effect of the missing non‐electrostatic repulsion of the MM region on result accuracy is showcased. While ESO errors are not readily visible for one‐photon absorption spectra, they become significant when computing two‐photon absorption, as more than one excited state is considered. Including ECPs on environment atoms sufficiently addresses the ESO problem, yielding correct structure for excited states. Comparisons with the more advanced PDE model show that PE‐ECP leads to qualitatively correct one‐ and two‐photon absorption spectra.

Nuclear Magnetic Shielding Constants with the Polarizable Density Embedding Model

“…Figure shows chemical shieldings of the HMT molecule in a DNA environment. The HMT structures are taken from ref and are obtained from an MD trajectory, followed by QM/MM minimization. The solvation effect on the shieldings can be attributed to two sources: (1) a direct effect caused by the coupling between the QM system and the environment and (2) an indirect geometrical effect due to the sampling of structures from an MD trajectory.…”

“…We computed shieldings of the 4′-(Hydroxymethyl)-4,5′,8-trimethylpsoralen (HMT) molecule in a DNA environment (see Figure ). The structures are taken from ref , where the system was shown to suffer from severe electron spill-out problems . We computed shieldings of the HMT molecule across the trajectory of 50 snapshots using CAMB3LYP/6-31+G*.…”

“…The structures are taken from ref 46, where the system was shown to suffer from severe electron spill-out problems. 46 We computed shieldings of the HMT molecule across the trajectory of 50 snapshots using CAMB3LYP/6-31+G*. The environment was either ignored or represented using PE or PDE.…”

“…The PDE model improves upon the PE model by (1) using a more accurate description of the classical electrostatics and (2) including an account of non-classical repulsion effects. The inclusion of the repulsion operator has been demonstrated as a possible solution to the problem of electron spill-out in QM/MM calculations. , In this paper, we implement the additional terms needed for calculating the shielding constants using GIAOs with the PDE model. We apply the PE and PDE models to several medium-sized bio-organic compounds to determine the basis set convergence behavior and QM region size requirements.…”

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

“…The formation of intra- and inter-DNA cross-links have been tackled in the literature by using both static and dynamic computational methods. For instance, previous studies unravelled the reactivity that leads to the formation of inter- and intrastrand cross-links through a static quantum mechanics (QM) approach in model systems. − Other works, explicitly accounting for the biological environments through classical molecular dynamics (MD) − and quantum mechanics/molecular mechanics (QM/MM) methods, − have assessed the impact of the cross-links on the DNA double strand helix dynamics. This is for instance relevant to find correlations between structural properties and difficulties in the cellular repair of the DNA lesions .…”