Evaluation of All-Atom\nand Martini 3 Coarse-Grained\nForce Fields from the Structural Investigation of Nitroxide Spin Probes\nand Their Confinement in Beta-Cyclodextrin

Nitroxide radicals have found wide applications as spin\nlabels\nor probes, and their guest–host interactions with cyclodextrins\nexhibit enhanced applications in electron spin resonance (ESR) spectroscopy\nand imaging due to improved biostability toward reducing agents. Although\nthe computational prediction of the guest–host binding has\nbecome increasingly common for small ligands, molecular simulations\nregarding the conformational preferences of hosted spin probes have\nnot been conducted. Here we present molecular dynamics simulations\nat an atomistic level for a set of four TEMPO (2,2,6,6-tetramethylpiperidine\n1-oxyl) spin probes and thereafter develop coarse-grained models compatible\nwith the recent version of the Martini force field (v 3.0) to tackle\ntheir encapsulation in the cavity of β-cyclodextrin (βCD)\nfor which experimental ESR data are available. The results indicate\nthat the atomistic descriptions perform well in relation to the structural\nparameters derived from X-ray diffraction as well as hydrogen bonding\nand hydrogen patterns and predict that the guest–host complexation\nis hydrophobically driven by the presence of a methyl group pair of\nthe spin probe at the cavity center of βCD. The spin probe mobility\nat the binding site reveals the nitroxide group orientation toward\nthe secondary rim of the cyclodextrin and the alternating presence\nof the two methyl group pairs inside the cavity, features in agreement\nwith the experimental behavior of the ESR parameters. The coarse-grained\nparameterizations of TEMPO probes and βCD rely on optimizing\nthe bonded and nonbonded parameters with references to the atomistic\nsimulation results, and they are capable of recovering the orientation\nand location of the spin probe inside the cyclodextrin cavity predicted\nby the atomistic guest–host complexes. The results suggest\nthe cyclodextrin host–guest system as a powerful validation\nsuite to evaluate new coarse-grained parameterizations of small ligands\nand future extensions to functionalized cyclodextrins in inclusion\ncomplexes.