Development of AMOEBA Polarizable Force Field for Rare-Earth La3+ Interaction with Bioinspired Ligands.

Rare-earth metals (REMs) are crucial for many important industries, such as power generation and storage, in addition to cancer treatment and medical imaging. One promising new REM refinement approach involves mimicking the highly selective and efficient binding of REMs observed in relatively recently discovered proteins. However, realizing any such bioinspired approach requires an understanding of the biological recognition mechanisms. Here, we developed a new classical polarizable force field based on the AMOEBA framework for modeling a lanthanum ion (La3+) interacting with water, acetate, and acetamide, which have been found to coordinate the ion in proteins. The parameters were derived by comparing to high-level ab initio quantum mechanical (QM) calculations that include relativistic effects. The AMOEBA model, with advanced atomic multipoles and electronic polarization, is successful in capturing both the QM distance-dependent La3+-ligand interaction energies and experimental hydration free energy. A new scheme for pairwise polarization damping (POLPAIR) was developed to describe the polarization energy in La3+ interactions with both charged and neutral ligands. Simulations of La3+ in water showed water coordination numbers and ion-water distances consistent with previous experimental and theoretical findings. Water residence time analysis revealed both fast and slow kinetics in water exchange around the ion. This new model will allow investigation of fully solvated lanthanum ion-protein systems using GPU-accelerated dynamics simulations to gain insights on binding selectivity, which may be applied to the design of synthetic analogues.

Automation of AMOEBA polarizable force field for small molecules: Poltype 2.

A next-generation protocol (Poltype 2) has been developed which automatically generates AMOEBA polarizable force field parameters for small molecules. Both features and computational efficiency have been drastically improved. Notable advances include improved database transferability using SMILES, robust torsion fitting, non-aromatic ring torsion parameterization, coupled torsion-torsion parameterization, Van der Waals parameter refinement using ab initio dimer data and an intelligent fragmentation scheme that produces parameters with dramatically reduced ab initio computational cost. Additional improvements include better local frame assignment for atomic multipoles, automated formal charge assignment, Zwitterion detection, smart memory resource defaults, parallelized fragment job submission, incorporation of Psi4 quantum package, ab initio error handling, ionization state enumeration, hydration free energy prediction and binding free energy prediction. For validation, we have applied Poltype 2 to ~1000 FDA approved drug molecules from DrugBank. The ab initio molecular dipole moments and electrostatic potential values were compared with Poltype 2 derived AMOEBA counterparts. Parameters were further substantiated by calculating hydration free energy (HFE) on 40 small organic molecules and were compared with experimental data, resulting in an RMSE error of 0.59 kcal/mol. The torsion database has expanded to include 3543 fragments derived from FDA approved drugs. Poltype 2 provides a convenient utility for applications including binding free energy prediction for computational drug discovery. Further improvement will focus on automated parameter refinement by experimental liquid properties, expansion of the Van der Waals parameter database and automated parametrization of modified bio-fragments such as amino and nucleic acids.

Catalytic Effect of Carbon Dioxide on Reaction OH + CO → H + CO2 in Supercritical Environment: Master Equation Study.

We investigated the reaction rates of OH + CO → H + CO2 in supercritical CO2 environment with and without additional CO2 molecule included in reactive complex. Ab initio potential energy surfaces previously reported a lower activation barrier and hence a catalytic effect of additional CO2 molecule. Here we solve the steady-state unimolecular master equations based on the Rice-Ramsperger-Kassel-Marcus theory (RRKM) and compare the rates for the two mechanisms. We found that the alternative reaction mechanism becomes faster at high pressure and low temperature, when the concentration of prereactive complex with additional CO2 molecule becomes appreciable. Therefore, this catalytic effect may be important for the chemical processes in CO2 solvent but is unlikely to play a role during combustion.

Quantum Chemical Study of CH3 + O2 Combustion Reaction System: Catalytic Effects of Additional CO2 Molecule.

The supercritical carbon dioxide diluent is used to control the temperature and to increase the efficiency in oxycombustion fossil fuel energy technology. It may affect the rates of combustion by altering mechanisms of chemical reactions, compared to the ones at low CO2 concentrations. Here, we investigate potential energy surfaces of the four elementary reactions in the CH3 + O2 reactive system in the presence of one CO2 molecule. In the case of reaction CH3 + O2 → CH2O + OH (R1 channel), van der Waals (vdW) complex formation stabilizes the transition state and reduces the activation barrier by ∼2.2 kcal/mol. Alternatively, covalently bonded CO2 may form a six-membered ring transition state and reduce the activation barrier by ∼0.6 kcal/mol. In case of reaction CH3 + O2 → CH3O + O (R2 channel), covalent participation of CO2 lowers the barrier for the rate limiting step by 3.9 kcal/mol. This is expected to accelerate the R2 process, important for the branching step of the radical chain reaction mechanism. For the reaction CH3 + O2 → CHO + H2O (R3 channel) with covalent participation of CO2, the activation barrier is lowered by 0.5 kcal/mol. The reaction CH2O + OH → CHO + H2O (R4 channel) involves hydrogen abstraction from formaldehyde by OH radical. Its barrier is reduced from 7.1 to 0.8 kcal/mol by formation of vdW complex with spectator CO2. These new findings are expected to improve the kinetic reaction mechanism describing combustion processes in supercritical CO2 medium.

Quantum Chemical Study of Supercritical Carbon Dioxide Effects on Combustion Kinetics.

In oxy-fuel combustion, the pure oxygen (O2), diluted with CO2 is used as oxidant instead air. Hence, the combustion products (CO2 and H2O) are free from pollution by nitrogen oxides. Moreover, high pressures result in the near-liquid density of CO2 at supercritical state (sCO2). Unfortunately, the effects of sCO2 on the combustion kinetics are far from being understood. To assist in this understanding, in this work we are using quantum chemistry methods. Here we investigate potential energy surfaces of important combustion reactions in the presence of the carbon dioxide molecule. All transition states and reactant and product complexes are reported for three reactions: H2CO + HO2 → HCO + H2O2 (R1), 2HO2 → H2O2 + O2 (R2), and CO + OH → CO2 + H (R3). In reaction R3, covalent binding of CO2 to the OH radical and then the CO molecule opens a new pathway, including hydrogen transfer from oxygen to carbon atoms followed by CH bond dissociation. Compared to the bimolecular OH + CO mechanism, this pathway reduces the activation barrier by 5 kcal/mol and is expected to accelerate the reaction. In the case of hydroperoxyl self-reaction 2HO2 → H2O2 + O2 the intermediates, containing covalent bonds to CO2 are found not to be competitive. However, the spectator CO2 molecule can stabilize the cyclic transition state and lower the barrier by 3 kcal/mol. Formation of covalent intermediates is also discovered in the H2CO + HO2 → HCO + H2O2 reaction, but these species lead to substantially higher activation barriers, which makes them unlikely to play a role in hydrogen transfer kinetics. The van der Waals complexation with carbon dioxide also stabilizes the transition state and reduces the reaction barrier. These results indicate that the CO2 environment is likely to have a catalytic effect on combustion reactions, which needs to be included in kinetic combustion mechanisms in supercritical CO2.

Chemical Reaction CO+OH(•) → CO2+H(•) Autocatalyzed by Carbon Dioxide: Quantum Chemical Study of the Potential Energy Surfaces.

The supercritical carbon dioxide medium, used to increase efficiency in oxy combustion fossil energy technology, may drastically alter both rates and mechanisms of chemical reactions. Here we investigate potential energy surface of the second most important combustion reaction with quantum chemistry methods. Two types of effects are reported: formation of the covalent intermediates and formation of van der Waals complexes by spectator CO2 molecule. While spectator molecule alter the activation barrier only slightly, the covalent bonding opens a new reaction pathway. The mechanism includes sequential covalent binding of CO2 to OH radical and CO molecule, hydrogen transfer from oxygen to carbon atoms, and CH bond dissociation. This reduces the activation barrier by 11 kcal/mol at the rate-determining step and is expected to accelerate the reaction rate. The finding of predicted catalytic effect is expected to play an important role not only in combustion but also in a broad array of chemical processes taking place in supercritical CO2 medium. It may open a new venue for controlling reaction rates for chemical manufacturing.

The impact of brief parental anxiety management on child anxiety treatment outcomes: a controlled trial.

Parental anxiety is a risk to optimal treatment outcomes for childhood anxiety disorders. The current trial examined whether the addition of a brief parental anxiety management (BPAM) program to family cognitive behavioral therapy (CBT) was more efficacious than family CBT-only in treating childhood anxiety disorders. Two hundred nine children (aged 6-13 years, 104 female, 90% Caucasian) with a principal anxiety disorder were randomly allocated to family CBT with a five-session program of BPAM (n = 109) or family CBT-only (n = 100). Family CBT comprised the Cool Kids program, a structured 12-week program that included both mothers and fathers. Overall, results revealed that the addition of BPAM did not significantly improve outcomes for the child or the parent compared to the CBT-only group at posttreatment or 6-month follow-up. Overall, however, children with nonanxious parents were more likely to be diagnosis free for any anxiety disorder compared to children with anxious parents at posttreatment and 6-month follow-up. BPAM did not produce greater reductions in parental anxiety. The results support previous findings that parent anxiety confers poorer treatment outcomes for childhood anxiety disorders. Nevertheless the addition of BPAM anxiety management for parents in its current format did not lead to additional improvements when used as an adjunct to family CBT in the treatment of the child's anxiety disorder. Future benefits may come from more powerful methods of reducing parents' anxiety.

Psychometric properties of the mini-social phobia inventory.

OBJECTIVE: Although a potentially useful measure, to date, there has been only one published test of the psychometric properties of the Mini-Social Phobia Inventory (Mini-SPIN). Therefore, the psychometric properties of the Mini-SPIN, a brief 3-item screen for social anxiety disorder, were examined. METHOD: Participants were 186 patients diagnosed with social anxiety disorder (DSM-IV criteria) attending a specialized anxiety disorders clinic for treatment, and 56 nonclinical participants were recruited to serve as comparisons. Participants were diagnosed using the Anxiety Disorders Interview Schedule for DSM-IV, and they also completed the Mini-SPIN, the Social Interaction Anxiety Scale (SIAS), and the Social Phobia Scale (SPS). Construct validity for the Mini-SPIN was assessed by its correlations with the SIAS and the SPS. Reliability, internal consistency, discriminant validity, and sensitivity to change were also examined, and receiver operating characteristic curve analysis was conducted to determine guidelines regarding cutoff scores for the Mini-SPIN. The study was conducted between April 1999 and December 2001. RESULTS: Supporting findings from a previous study, strong support was found for the Mini-SPIN's ability to discriminate individuals with social anxiety disorder from those without the disorder. Receiver operating characteristic analysis revealed that using a cutoff score of 6 or greater (P < .001), the Mini-SPIN demonstrates excellent sensitivity, specificity, and positive and negative predictive values. CONCLUSIONS: Findings suggest that the Mini-SPIN is a reliable and valid instrument for screening social anxiety disorder in adults. Importantly, the use of the Mini-SPIN in primary care may be one way to address the underrecognition of social anxiety disorder in such settings. Due to the ease and brevity of the measure, it also shows potential for use in epidemiology. Given that this study has revealed the ability of the Mini-SPIN to reflect treatment change, the Mini-SPIN may also be considered for use in treatment outcome studies that specifically require minimal assessment.