Evaluation of All-Atom and Martini 3 Coarse-Grained Force Fields from the Structural Investigation of Nitroxide Spin...

Nitroxide radicals have found wide applications as spin labels or probes, and their guest-host interactions with cyclodextrins exhibit enhanced applications in electron spin resonance (ESR) spectroscopy and imaging due to improved biostability toward reducing agents. Although the computational prediction of the guest-host binding has become increasingly common for small ligands, molecular simulations regarding the conformational preferences of hosted spin probes have not been conducted. Here we present molecular dynamics simulations at an atomistic level for a set of four TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) spin probes and thereafter develop coarse-grained models compatible with the recent version of the Martini force field (v 3.0) to tackle their encapsulation in the cavity of β-cyclodextrin (βCD) for which experimental ESR data are available. The results indicate that the atomistic descriptions perform well in relation to the structural parameters derived from X-ray diffraction as well as hydrogen bonding and hydrogen patterns and predict that the guest-host complexation is hydrophobically driven by the presence of a methyl group pair of the spin probe at the cavity center of βCD. The spin probe mobility at the binding site reveals the nitroxide group orientation toward the secondary rim of the cyclodextrin and the alternating presence of the two methyl group pairs inside the cavity, features in agreement with the experimental behavior of the ESR parameters. The coarse-grained parameterizations of TEMPO probes and βCD rely on optimizing the bonded and nonbonded parameters with references to the atomistic simulation results, and they are capable of recovering the orientation and location of the spin probe inside the cyclodextrin cavity predicted by the atomistic guest-host complexes. The results suggest the cyclodextrin host-guest system as a powerful validation suite to evaluate new coarse-grained parameterizations of small ligands and future extensions to functionalized cyclodextrins in inclusion complexes.