The dynamics of the HBr + + CO 2 → HOCO + + Br reaction was recently investigated with guided ion beam experiments under various excitations (collision energy of the reactants, rotational and spin−orbital states of HBr + , etc.), and their impacts were probed through the change of the cross section of the reaction. The potential energy profile of this reaction has also been accurately characterized by high-level ab initio methods such as CCSD(T)/CBS, and the UMP2/cc-pVDZ/lanl08d has been identified as an ideal method to study its dynamics. This manuscript reports the first ab initio molecular dynamics simulations of this reaction at two different collision energies, 8.1 kcal/mol and 19.6 kcal/mol. The cross sections measured from the simulations agree very well with the experiments measured with HBr + in the 2 ∏ 1/2 state. The simulations reveal three distinct mechanisms at both collision energies: direct rebound (DR), direct stripping (DS), and indirect (Ind) mechanisms. DS and Ind make up 97% of the total reaction. The dynamics of this reaction is also compared with nucleophilic substitution (S N 2) reactions of X − + CH 3 Y → CH 3 X + Y − type. In summary, this research has revealed interesting dynamics of the HBr + + CO 2 → HOCO + + Br reaction at different collision energies and has laid a solid foundation for using this reaction to probe the impact of rotational excitation of ion−molecule reactions in general.

A protocol that accurately assesses the intestinal permeability of small molecule compounds plays an essential role in decreasing the cost and time in inventing a new drug. This manuscript presents a novel computational method to study the passive permeation of small molecule drugs based on the inhomogeneous solubility-diffusion model. The multidimensional free energy surface of the drug transiting through a lipid bilayer is computed with transition-tempered metadynamics that accurately captures the mechanisms of passive permeation. The permeability is computed by following the diffusion motion of the drug molecules along the minimal free energy path found on the multidimensional free energy surface. This computational method is assessed by studying the permeability of five small molecule drugs (ketoprofen, naproxen, metoprolol, propranolol, and salicylic acid). The results demonstrate a remarkable agreement between the computed permeabilities and those measured with the intestinal assay. The in silico method reported in this manuscript also reproduces the permeability measured from the intestinal assay (in vivo) better than the cell-based assays (e.g., PAMPA and Caco-2) do. In addition, the multidimensional free energy surface reveals the interplay between the structure of the small molecule and its permeability, shedding light on strategies of drug optimization.

Recent guided ion beam experiments have revealed interesting reaction dynamics of the HBr + + CO 2 → HOCO + + Br• reaction under different conditions. The hypothesis is that the predominant reaction mechanism depends on the collision energy between two reactants, the angular momentum of HBr + , and the spin− orbit coupling state of the system. The potential energy profile of the HBr + + CO 2 → HOCO + + Br• reaction is studied in this research to lay the groundwork for an ab initio molecular dynamics simulation. First, a benchmark potential energy profile of this reaction is identified using coupled-cluster theory extrapolated to the complete basis set limit. A transition state connecting the previously reported intermediates is found, making the potential energy surface of the HBr + + CO 2 → HOCO + + Br• reaction double-welled. Second, various single reference ab initio methods are compared with the benchmark potential energy profile to search for the most suitable ab initio method for the dynamics simulation. Two combinations of double-ζ basis sets (with effective core potentials) with MP2 and density functional theory have been identified to accurately represent the potential energy profile of this reaction.