Daniel L. Severance

Limited effects of polarization for Cl−(H2O)n and Na+(H2O)n clusters

Monte Carlo statistical mechanics simulations have been carried out for Cl− and Na+ in clusters of 1–14 water molecules. OPLS potential functions were used including the TIP4P model of water that do not include explicit polarization effects. In contrast to a prior report with the same potential functions, the computed enthalpies of binding for Cl− are shown to agree closely with experimental data, while the values for Na+ are about 10% too exothermic. The latter discrepancy is largely removed by using Aqvist’s Na+ parameters with TIP3P water. Moreover, the structures of the clusters show the expected nonspherical distribution of water molecules.

Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors that are Orally Active in Rodent Pain Models

There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42--potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.

Multiphoton ionization studies of C6H6–(CH3OH)n clusters. I. Comparisons with C6H6–(H2O)n clusters

Resonant two‐photon ionization (R2PI) scans of the S0–S1 spectra of C6H6–(CH3OH)n clusters with n=1–5 have been recorded. These scans provide an interesting comparison with earlier spectra from our laboratory on C6H6–(H2O)n clusters. A variety of vibronic level arguments are used to constrain the geometries of the C6H6–(CH3OH)n clusters. The 1:1 and 1:2 clusters possess vibronic level features which are very similar to their aqueous counterparts. The 1:1 cluster places the methanol molecule in a π hydrogen‐bonded configuration on or near the sixfold axis of benzene. The spectral characteristics of the 1:2 cluster are consistent with both methanol molecules residing on the same side of the benzene ring as a methanol dimer. Higher C6H6–(CH3OH)n clusters show distinct differences from the corresponding C6H6–(H2O)n clusters. Vibronic level arguments lead to the following conclusions: the methanol molecules in the 1:3 cluster show the strongest hydrogen bonding to the π cloud of any of the clusters and attach ...

Investigation of solvent effects on pericyclic reactions by computer simulations

A combination of quantum and statistical mechanics is being used to probe the origins of solvent effects on the kinetics of organic reactions. Ab initio molecular orbital calculations provide gas-phase reaction paths and partial charges for the reacting systems. The reaction paths are then followed by Monte Carlo simulations in periodic cells containing hundreds of solvent molecules, and the changes in Gibbs free energies of solvation are obtained. Results are provided for several prototypical pericyclic reactions : Diels–Alder cycloadditions for methyl vinyl ketone with cyclopentadiene and the dimerization of cyclopentadiene, the Claisen rearrangement of allyl vinyl ether, and the electrocyclic ring opening of cyclopropanones to oxyallyls. Detailed insights are obtained on issues such as the acceleration of the Diels–Alder reactions and Claisen rearrangement in water, and the electronic nature of oxyallyls.

The structure and photophysics of clusters of immiscible liquids: C6H6(H2O)n

Abstract Mixed clusters of C 6 H 6 and H 2 O type of C 6 H 6 (H 2 O) n where n = 1–5 have been studied using one-color resonance-enhanced two-photon ionization coupled with time-of-flight mass spectrometric detection. The 1:1 complex is seen to have an electronically forbidden origin with intensity at least 1000 times less than that at 6 1 0 . The H 2 O molecule thus lies on the sixfold axis of benzene and is undergoing free radical rotation about this axis. The blue-shift and high-efficiency of fragmentation of the 1:1 complex argue for hydrogen bonding of the H 2 O molecule to the benzene π cloud. The 1:2 complex induces a strong origin with intensity 14% of that at 6 1 0 . The rotational band contour yields a geometry in which the two water molecules bind to benzene on one side of the benzene ring, with a H 2 OH 2 O separation close to that in the water dimer. Higher 1: n clusters show spectra which suggest structures involving a network of hydrogen bonded water molecules building up away from the benzene ring, consistent with a microscopic immiscibility of C 6 H 6 and H 2 O.

GENERALIZED ALTERATION OF STRUCTURE AND PARAMETERS: A NEW METHOD FOR FREE-ENERGY PERTURBATIONS IN SYSTEMS CONTAINING FLEXIBLE DEGREES OF FREEDOM

A modified derivation of the free energy perturbation (FEP) equation leads to a more general interpretation of the procedures for generating the geometry of a perturbed molecule from the reference one in FEP simulations of flexible systems. Using this form of the equation, it is possible to implement a wide variety of procedures which heretofore would have been considered impossible. A new method, generalized alteration of structure and parameters (GASP), has been implemented in the BOSS program and has been found to be more efficient for perturbations of harmonic degrees of freedom than the commonly adopted procedure. Additionally, an extreme example for which the new procedure proves less satisfactory is presented, and a more efficient method which is also derived from the new form of the FEP equation is devised and tested. It is concluded that the key to a convergent FEP method is efficient sampling of low‐energy configurations of the perturbed state; the new form of the equation suggests ways of generating such configurations.

Approaches to Protein-Ligand Binding from Computer Simulations

Accurate computation of protein-ligand binding affinities is a challenging goal with great potential value in the design of therapeutic agents. Applications of statistical mechanics simulations to the problem are considered that feature full atomic-level descriptions of the protein, ligand and aqueous environment. Basic concepts on the methodology and intermolecular interactions in solution are presented along with results of Monte Carlo simulations for binding of inhibitors by trypsin and thrombin.

Theoretical analyses of hydrogen abstraction by aldehyde triplet excited states

Abstract The fully optimized transition states for hydrogen abstraction from methane by formaldehyde and acetaldehyde have been computed using UMP2/6-31G(d)//6-31G(d) calculations. The geometry of the formaldehyde/methane transition state matches well with the geometry obtained previously using the 3-21G basis set, but the energy is lowered somewhat (18.7 versus 22 kcal/mol, respectively). Approach of the methane trans-periplanar (i.e. anti) to the acetaldehyde methyl group leads to a transition state similar to that for formaldehyde (saddle point at 17.9 kcal/mol). Approach syn to the methyl group leads to a modest variation in both the saddle point geometry and energy (19.1 kcal/mol), both attributed to unfavorable steric interactions in this trajectory.

Modeling Interactions with Benzene: Aryl-Aryl, Cation-π, and Chaotrope-π

The association of benzene with itself, urea, guanidinium ion, and tetramethylammonium ion has been studied in water via Monte Carlo statistical mechanics simulations. Benzene dimerization in chloroform and liquid benzene have also been considered as well as the association of urea with naphthalene in water. Calculations of potentials of mean force predict complexes to exist in each case at contact separations. The energetics and optimal structures for the gas-phase complexes have also been characterized. Differences with the solution structures are discussed along with general implications for host-guest chemistry.