Toward theoretical analysis of long-range proton transfer kinetics in biomolecular pumps.

Motivated by the long-term goal of theoretically analyzing long-range proton transfer (PT) kinetics in biomolecular pumps, researchers made a number of technical developments in the framework of quantum mechanics-molecular mechanics (QM/MM) simulations. A set of collective reaction coordinates is proposed for characterizing the progress of long-range proton transfers; unlike previous suggestions, the new coordinates can describe PT along highly nonlinear three-dimensional pathways. Calculations using a realistic model of carbonic anhydrase demonstrated that adiabatic mapping using these collective coordinates gives reliable energetics and critical geometrical parameters as compared to minimum energy path calculations, which suggests that the new coordinates can be effectively used as reaction coordinate in potential of mean force calculations for long-range PT in complex systems. In addition, the generalized solvent boundary potential was implemented in the QM/MM framework for rectangular geometries, which is useful for studying reactions in membrane systems. The resulting protocol was found to produce water structure in the interior of aquaporin consistent with previous studies including a much larger number of explicit solvent and lipid molecules. The effect of electrostatics for PT through a membrane protein was also illustrated with a simple model channel embedded in different dielectric continuum environments. The encouraging results observed so far suggest that robust theoretical analysis of long-range PT kinetics in biomolecular pumps can soon be realized in a QM/MM framework.

A critical evaluation of different QM/MM frontier treatments with SCC-DFTB as the QM method.

The performance of different link atom based frontier treatments in QM/MM simulations was evaluated critically with SCC-DFTB as the QM method. In addition to the analysis of gas-phase molecules as in previous studies, an important element of the present work is that chemical reactions in realistic enzyme systems were also examined. The schemes tested include all options available in the program CHARMM for SCC-DFTB/MM simulation, which treat electrostatic interactions due to the MM atoms close to the QM/MM boundary in different ways. In addition, a new approach, the divided frontier charge (DIV), has been implemented in which the partial charge associated with the frontier MM atom ("link host") is evenly distributed to the other MM atoms in the same group. The performance of these schemes was evaluated based on properties including proton affinities, deprotonation energies, dipole moments, and energetics of proton transfer reactions. Similar to previous work, it was found that calculated proton affinities and deprotonation energies of alcohols, carbonic acids, amino acids, and model DNA bases are very sensitive to the link atom scheme; the commonly used single link atom approach often gives error on the order of 15 to 20 kcal/mol. Other schemes give better and, on average, mutually comparable results. For proton transfer reactions, encouragingly, both activation barriers and reaction energies are fairly insensitive (within a typical range of 2-4 kcal/mol) to the link atom scheme due to error cancellation, and this was observed for both gas-phase and enzyme systems. Therefore, the effect of using different link atom schemes in QM/MM simulations is rather small for chemical reactions that conserve the total charge. Although the current study used an approximate DFT method as the QM level, the observed trends are expected to be applicable to QM/MM methods with use of other QM approaches. This observation does not mean to encourage QM/MM simulations without careful benchmark in the study of specific systems, rather it emphasizes that other technical details, such as the treatment of long-range electrostatics, tend to play a more important role and need to be handled carefully.

Hyperactive boys almost grown up. IV. Criminality and its relationship to psychiatric status.

Attention-deficit disorder with hyperactivity is believed, by some, to be a developmental antecedent (predisposing factor) to antisocial personality disorder and criminality. However, evidence supporting this association has not been consistent. We report on a prospective follow-up study of 103 males (ages 16 to 23 years), who were diagnosed as hyperactive (attention-deficit disorder with hyperactivity) between ages 6 and 12 years, and 100 normal controls. The official arrest records of all subjects who resided in New York State during the follow-up interval were obtained. Blind diagnoses (based on structured interviews with subjects and their parents) were made on 98% of the initial cohort at follow-up. Although other investigators have reported on the delinquent behavior of hyperactive children in a prospective design, to our knowledge, follow-up mental status has not been studied previously in relation to official arrest records. Significantly more probands than controls had been arrested (39% vs 20%), convicted (28% vs 11%), and incarcerated (9% vs 1%). The presence of an antisocial/conduct disorder in young adulthood almost completely accounted for the increased risk for criminal activities in the former hyperactive children whether or not it was accompanied by a substance use disorder. Continuing attention-deficit disorder with hyperactivity at follow-up, by itself, was not associated with arrest history. The findings support the view that childhood attention-deficit disorder with hyperactivity is a risk factor for later criminality, but that this relationship is almost exclusively mediated by the development of an antisocial disorder in early adulthood.

Hyperactive boys almost grown up. II. Status of subjects without a mental disorder.

In a previous article we reported the rate of DSM-III diagnoses among 101 male adolescents (aged 16 to 23 years) in whom hyperactivity had been diagnosed between ages 6 and 12 years compared with 100 controls. This report examines the rates of dysfunction among the 52 probands and 80 control adolescents who did not receive a DSM-III diagnosis at follow-up. Contrary to expectations, there were few areas (primarily involving school adjustment) in which the formerly hyperactive children were found to be at a disadvantage and numerous areas (occupational adjustment, temperament, alcohol abuse, antisocial activities, etc) in which the groups were indistinguishable. The results are explained in accordance with a bimodal distribution of dysfunction in hyperactive children grown up. Indirectly, this model supports the construct validity of the DSM-III diagnoses attention deficit disorder with hyperactivity, substance use disorder, and antisocial personality disorder. Post hoc analyses suggest that behavior problems resulting from drug use in early adolescence have graver consequences for previously hyperactive children than normal subjects.