Further Insights into the Environmental Effects on the Computed Hyperfine Coupling Constants of Nitroxides in Aqueous Solution

Abstract

We investigated the main two factors influencing the mean hyperfine coupling constants of small nitroxide radicals in aqueous solution, i.e., the out-of-plane displacement of their nitrogen atom and the environmental effects (solvent effects), by means of the approach we previously developed and fine-tuned to study the solvation of the dimethyl nitroxide radical. Our methodology efficiently combines classical molecular dynamics based on a polarizable force field at the nanosecond scale and quantum mechanics/molecular mechanics (QM/MM) computations to account for the bulk instantaneous electrostatic environmental effect. Our method has been applied to five small nitroxides, namely methyl nitroxide, ethyl nitroxide, dimethyl nitroxide, di-tert-butyl nitroxide, and PROXYL. The theoretical nitrogen hyperfine coupling constant values for the five nitroxides in solution are in good agreement with experiment (difference of 0.3 G on average). Our approach showed that the solvent shift in nitroxide hyperfine coupling constants is almost constant whatever the nitroxide, and, particularly, whatever the nitroxide NO moiety's accessibility to the solvent. This result contrasts with earlier results derived from 10 ps scale trajectories based on Car-Parrinello molecular dynamics approach. However, we show that if we consider on average these latter results, they are in agreement with our conclusion. We also present an attempt to identify the origin of this result by analyzing the solvent contributions in terms of effects of the nitroxide first hydration shell and of the bulk, and by investigating the relation between these two contributions and the solvent structure at the vicinity of the NO moiety.

Assessing the accuracy of a QM/MM//MD combined protocol to compute spectromagnetic properties of polyfunctional nitroxides in solution

“…For the remaining trajectories, g 2D (h,/) appears to be the average of T1 and T8, weighted by the p 3T4 and p 4T3 values. Concerning \ONCC, its distribution functions correspond to Gaussian profiles centered around 170-175°, with almost negligible contributions for h \ 150°and h [ 210°, similar to the case of the PROXYL and DMPO-OOH nitroxides we recently investigated [2,8].…”

“…On the contrary, the solvent contribution for " a H c is negligible (between -0.1 and 0.2 Gauss). The reliability of our PBE0 hcc computations is checked by evaluating the da X quantum quantum uncertainty as in our previous works [2,8]. Based on the (h, /) hcc contours in gas phase corresponding to the MENO-OH model radical and on the (h, /) 2D distributions computed from the solvated trajectories, we interpolate both the CCSD/EPR-II and PBE0/6-31?G(d) hcc's in gas phase using a bicubic interpolation scheme.…”

“…Recently, we proposed such a protocol to compute hyperfine coupling constants (hcc's) of flexible nitroxides in water [1,2]. It is based on combining nanosecond-scale classical molecular dynamics (MD) with large-scale QM/MM computations on small nitroxide/ water clusters extracted along the MD trajectories.…”

π-Stacking effects on the EPR parameters of a prototypical DNA spin label

“…[19][20][21][22] Differently from the chemical processes responsible for the reduction of nitroxide spin labels to EPR silent diamagnetic molecules, the behaviour of magnetic properties of spin labels in DNA environment has been scarcely studied. Furthermore, among a vast number of theoretical studies [23][24][25][26][27][28][29][30][31][32] devoted to environmental effects on EPR spin Hamiltonian parameters of nitroxides, only a few have ventured beyond the investigation of simple aprotic and protic solvent environments. Recently, we carried out such studies of magnetic properties of nitroxide spin labels bound to proteins 33 and encapsulated in "guest-host" complexes 31,32 .…”

An integrated computational protocol for the accurate prediction of EPR and PNMR parameters of aminoxyl radicals in solution

“…However, in both cases, the interpretation of the rich, indirect information that can be inferred from the analysis of the experimental spectra is seldom straightforward since the magnetic properties of a radical depend on the subtle interplay between several different effects. In such a complex scenario, theoretical studies can be very useful by supporting and complementing the experimental results to determine the electronic and geometric structure of the radical under investigation starting from its spectral properties and dissecting and evaluating the role of different effects in determining its magnetic properties 5, 12–17…”