Quantum Chemistry of Cocaine and its Isomers I: Energetics, Reactivity and Solvation

ABSTRACT We investigate the rich stereochemistry of cocaine and its diastereoisomers from a theoretical perspective using density functional theory. The relative stability of the eight considered isomers is discussed, and a comparison of the corresponding internal coordinates is given. Our results reveal that the S-pseudococaine isomer is the most stable conformation, whereas the natural occurring isomer (R-cocaine) lies higher in energy. The different isomers' chemical reactivity is discussed based on the calculation of the hardness, softness, electrophilicity and dipole moment. It was found that the dipole moment varies over a broad range from 0.65 to 4.60 D, whereas the other properties are slightly modified. The solvent effect on the energy stability of the cocaine isomers was studied by considering chloroform, dimethyl-sulfoxide (DMSO) and water as implicit solvents. Our calculations show that the different isomers' energy order and their energy gaps are slightly modified due to solvent effects. However, in all cases, the S-pseudococaine remains the most stable isomer. However, the dipole moment and the chemical reactivity of the cocaine isomers increase with the solvent polarity. Keywords: Cocaine isomers,DFT, stability, solvent effect, chemical reactivity.

Implicit Solvents for the Polarizable Atomic Multipole AMOEBA Force Field

Computational protein design, ab initio protein/RNA folding, and protein-ligand screening can be too computationally demanding for explicit treatment of solvent. For these applications, implicit solvent offers a compelling alternative, which we describe here for the polarizable atomic multipole AMOEBA force field based on three treatments of continuum electrostatics: numerical solutions to the Poisson-Boltzmann equation (PBE), the domain-decomposition Conductor-like Screening Model (ddCOSMO) approximation to the PBE, and the analytic generalized Kirkwood (GK) approximation. The continuum electrostatic models are combined with a nonpolar estimator based on novel cavitation and dispersion terms. Electrostatic model parameters are numerically optimized using a least squares style target function based on a library of 103 small molecule solvation free energy differences. Mean signed errors for the APBS, ddCOSMO, and GK models are 0.05, 0.00, and 0.00 kcal/mol, respectively, while the mean unsigned errors are 0.70, 0.63, and 0.51 kcal/mol, respectively. Validation of the electrostatic response of the resulting implicit solvents, which are available in the Tinker (or Tinker-HP), OpenMM, and Force Field X software packages, is based on comparisons to explicit solvent simulations for a series of proteins and nucleic acids. Overall, the emergence of performative implicit solvent models for polarizable force fields will open the door to their use for folding and design applications.<br>

Implicit Solvents for the Polarizable Atomic Multipole AMOEBA Force Field

Computational protein design, ab initio protein/RNA folding, and protein-ligand screening can be too computationally demanding for explicit treatment of solvent. For these applications, implicit solvent offers a compelling alternative, which we describe here for the polarizable atomic multipole AMOEBA force field based on three treatments of continuum electrostatics: numerical solutions to the Poisson-Boltzmann equation (PBE), the domain-decomposition Conductor-like Screening Model (ddCOSMO) approximation to the PBE, and the analytic generalized Kirkwood (GK) approximation. The continuum electrostatic models are combined with a nonpolar estimator based on novel cavitation and dispersion terms. Electrostatic model parameters are numerically optimized using a least squares style target function based on a library of 103 small molecule solvation free energy differences. Mean signed errors for the APBS, ddCOSMO, and GK models are 0.05, 0.00, and 0.00 kcal/mol, respectively, while the mean unsigned errors are 0.70, 0.63, and 0.51 kcal/mol, respectively. Validation of the electrostatic response of the resulting implicit solvents, which are available in the Tinker (or Tinker-HP), OpenMM, and Force Field X software packages, is based on comparisons to explicit solvent simulations for a series of proteins and nucleic acids. Overall, the emergence of performative implicit solvent models for polarizable force fields will open the door to their use for folding and design applications.<br>

A Mechanistic Study on the Tautomerism of H-Phosphonates, H-Phosphinates and Secondary Phosphine Oxides

H-phosphonates, H-phosphinates and secondary phosphine oxides may be preligands, and are important building blocks in the synthesis of pharmaceuticals, pesticides, and P-ligands. The prototropic tautomerism influenced by substituent effects plays an important role in the reactivity of these species. The main goal of our research was to study the tautomerism of the >P(O)H reagents by means of computational investigations applying several DFT methods at different levels. We focused on the effect of implicit solvents, and on explaining the observed trends with physical chemical molecular descriptors. In addition, multiple reaction pathways incorporating three P-molecules were elucidated for the mechanism of the interconversion.