Ion-orbital coupling in Car-Parrinello calculations of hydrogen-bond vibrational dynamics: case study with the NH3-HCl dimer.

We have performed Car-Parrinello molecular dynamics (CPMD) calculations of the hydrogen-bonded NH(3)-HCl dimer. Our main aim is to establish how ionic-orbital coupling in CPMD affects the vibrational dynamics in hydrogen-bonded systems by characterizing the dependence of the calculated vibrational frequencies upon the orbital mass in the adiabatic limit of Car-Parrinello calculations. We use the example of the NH(3)-HCl dimer because of interest in its vibrational spectrum, in particular the magnitude of the frequency shift of the H-Cl stretch due to the anharmonic interactions when the hydrogen bond is formed. We find that an orbital mass of about 100 a.u. or smaller is required in order for the ion-orbital coupling to be linear in orbital mass, and the results for which can be accurately extrapolated to the adiabatic limit of zero orbital mass. We argue that this is general for hydrogen-bonded systems, suggesting that typical orbital mass values used in CPMD are too high to accurately describe vibrational dynamics in hydrogen-bonded systems. Our results also show that the usual application of a scaling factor to the CPMD frequencies to correct for the effects of orbital mass is not valid. For the dynamics of the dimer, we find that the H-Cl stretch and the N-H-Cl bend are significantly coupled, suggesting that it is important to include the latter degree of freedom in quantum dynamical calculations. Results from our calculations with deuterium-substitution show that both these degrees of freedom have significant anharmonic interactions. Our calculated frequency for the H-Cl stretch using the Becke-exchange Lee-Yang-Parr correlation functional compares reasonably well with a previous second-order Møller-Plesset calculation with anharmonic corrections, although it is low compared to the experimental value for the dimer trapped in a neon-matrix.

Physics and the quandaries of contemporary psychiatry: review and research.

Although in physics, quantum mechanical principles have long replaced Newtonian ones, we continue to apply the latter in models of the mind and its diseases. This article discusses the possible theoretical application of quantum principles to mind-brain function. Empirically, this study tested which of these principles practicing psychiatrists found more applicable in clinical practice. Psychiatrists (N = 382) at universities around the United States were asked to answer a questionnaire that contained clinical scenarios reflecting mental, interpersonal, or therapeutic processes corresponding to quantum or classical physical principles. Respondents (N = 191) were significantly more likely to rate scenarios reflecting quantum principles as being consistent with their experience than they were those reflecting classical principles (p < .0005). This effect was significantly greater in more experienced psychiatrists. Quantum physics, a powerful tool in understanding properties of both micro- and macro-level phenomena, may have implications at the human level, invoking the roles of observer, interpersonal relationships, and resources such as resiliency and creativity.

A mutational analysis of residues essential for ligand recognition at the human P2Y1 receptor.

We conducted a mutational analysis of residues potentially involved in the adenine nucleotide binding pocket of the human P2Y1 receptor. Mutated receptors were expressed in COS-7 cells with an epitope tag that permitted confirmation of expression in the plasma membrane, and agonist-promoted inositol phosphate accumulation was assessed as a measure of receptor activity. Residues in transmembrane helical domains (TMs) 3, 5, 6, and 7 predicted by molecular modeling to be involved in ligand recognition were replaced with alanine and, in some cases, by other amino acids. The potent P2Y1 receptor agonist 2-methylthio-ATP (2-MeSATP) had no activity in cells expressing the R128A, R310A, and S314A mutant receptors, and a markedly reduced potency of 2-MeSATP was observed with the K280A and Q307A mutants. These results suggest that residues on the exofacial side of TM3 and TM7 are critical determinants of the ATP binding pocket. In contrast, there was no change in the potency or maximal effect of 2-MeSATP with the S317A mutant receptor. Alanine replacement of F131, H132, Y136, F226, or H277 resulted in mutant receptors that exhibited a 7-18-fold reduction in potency compared with that observed with the wild-type receptor. These residues thus seem to subserve a less important modulatory role in ligand binding to the P2Y1 receptor. Because changes in the potency of 2-methylthio-ADP and 2-(hexylthio)-AMP paralleled the changes in potency of 2-MeSATP at these mutant receptors, the beta- and gamma-phosphates of the adenine nucleotides seem to be less important than the alpha-phosphate in ligand/P2Y1 receptor interactions. However, T221A and T222A mutant receptors exhibited much larger reductions in triphosphate (89- and 33-fold versus wild-type receptors, respectively) than in diphosphate or monophosphate potency. This result may be indicative of a greater role of these TM5 residues in gamma-phosphate recognition. Taken together, the results suggest that the adenosine and alpha-phosphate moieties of ATP bind to critical residues in TM3 and TM7 on the exofacial side of the human P2Y1 receptor.

Mutagenesis reveals structure-activity parallels between human A2A adenosine receptors and biogenic amine G protein-coupled receptors.

Structure-affinity relationships for ligand binding at the human A2A adenosine receptor have been probed using site-directed mutagenesis in the transmembrane helical domains (TMs). The mutant receptors were expressed in COS-7 cells and characterized by binding of the radioligands [3H]CGS21680, [3H]NECA, and [3H]XAC. Three residues, at positions essential for ligand binding in other G protein-coupled receptors, were individually mutated. The residue V(3.32) in the A2A receptor that is homologous to the essential aspartate residue of TM3 in the biogenic amine receptors, i.e., V84(3.32), may be substituted with L (present in the A3 receptor) but not with D (in biogenic amine receptors) or A. H250(6.52), homologous to the critical N507 of rat m3 muscarinic acetylcholine receptors, may be substituted with other aromatic residues or with N but not with A (Kim et al. J. Biol. Chem. 1995, 270, 13987-13997). H278(7.43), homologous to the covalent ligand anchor site in rhodopsin, may not be substituted with either A, K, or N. Both V84L(3.32) and H250N(6.52) mutant receptors were highly variable in their effect on ligand competition depending on the structural class of the ligand. Adenosine-5'-uronamide derivatives were more potent at the H250N(6.52) mutant receptor than at wild type receptors. Xanthines tended to be close in potency (H250N(6.52)) or less potent (V84L(3.32)) than at wild type receptors. The affinity of CGS21680 increased as the pH was lowered to 5.5 in both the wild type and H250N(6.52) mutant receptors. Thus, protonation of H250(6.52) is not involved in this pH dependence. These data are consistent with a molecular model predicting the proximity of bound agonist ligands to TM3, TM5, TM6, and TM7.