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A multidisciplinary approach, based on mol. dynamics/mechanics, ab initio calcns., dynamic docking studies, and chem. reactions, has been employed to gain insight into the mechanism of the antimalarial action of plakortin and dihydroplakortin, simple 1,2-dioxanes isolated from the sponge Plakortis simplex. Our results show that these mols., after interaction of the endoperoxide bond with Fe(II), likely coming from the heme mol., give rise to the formation of an oxygen radical, followed by rearrangement to give a carbon radical centered on the "western" alkyl side-chain. The carbon radicals generated on the side-chain, amenable for intermol. reactions, should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The minimal structural requirements necessary for the activity of this class of antimalarial agents have been identified and discussed throughout the paper.

An integrated computational strategy for the evaluation of reliable structures and magnetic properties of spin probes and spin labels has been extended to aromatic species. From an electronic point of view, delocalization of the unpaired electron density over aromatic moieties reduces significantly the computed nitrogen isotropic hyperfine coupling constant (A(N)) with respect to values characteristic of aliphatic nitroxides. Solvent effects in not too high polarity media are quite small, but not negligible. At this stage computed A(N) are lower than their experimental counterparts by more than 1 G. Inclusion of vibrational averaging effects by molecular dynamics simulations with a new reliable force field restores full agreement with experiment pointing out the limits of static approaches irrespective of the sophistication of the electronic quantum mechanical method. The generality and computational effectiveness of the proposed integrated approach paves the route toward a reliable analysis of the interplay of stereo-electronic, environmental, and dynamical effects in tuning the properties of large flexible magnetic systems of biological and technological interest.

The popular AMBER force-field has been extended to provide an accurate description of large and flexible nitroxide free-radicals in condensed phases. New atom types have been included, and relevant parameters have been fitted based on geometries, vibrational frequencies and potential energy surfaces computed at the DFT level for several different classes of nitroxides, both in vacuo and in different solvents. The resulting computational tool is capable of providing reliable structures, vibrational frequencies, relative energies and spectroscopic observables for large and flexible nitroxide systems, including those typically used as spin labels. The modified force field has been employed in the context of an integrated approach, based on classical molecular dynamics and discrete-continuum solvent models, for the investigation of environmental and short-time dynamic effects on the hyperfine and gyromagnetic tensors of PROXYL, TEMPO and INDCO spin probes. The computed magnetic parameters are in very good agreement with the available experimental values, and the procedure allows for an unbiased evaluation of the role of different effects in tuning the overall EPR observables.