RESUMO
We have performed a parallel tempering crankshaft motion Monte Carlo simulation on a model of the GABA type A receptor with the aim of exploring a wide variety of local conformational space. We develop a novel method to analyse the protein movements in terms of a correlation tensor and use this to explore the gating process, that is, how agonist binding could cause ion channel opening. We find that simulated binding impulses to varying clusters of GABA binding site residues produce channel opening, and that equivalent impulses to single GABA sites produce partial opening.
Assuntos
Simulação de Dinâmica Molecular , Receptores de GABA-A/química , Sítios de Ligação , Humanos , Método de Monte Carlo , Conformação ProteicaRESUMO
We have performed docking simulations on GABARAP interacting with the GABA type A receptor using SwarmDock. We have also used a novel method to study hydration sites on the surface of these two proteins; this method identifies regions around proteins where desolvation is relatively easy, and these are possible locations where proteins can bind each other. There is a high degree of consistency between the predictions of these two methods. Moreover, we have also identified binding sites on GABARAP for other proteins, and listed possible binding sites for as yet unknown proteins on both GABARAP and the GABA type A receptor intracellular domain.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Associadas aos Microtúbulos/química , Simulação de Acoplamento Molecular , Receptores de GABA-A/química , Proteínas Reguladoras de Apoptose , Sítios de Ligação , Bases de Dados de Proteínas , Humanos , Conformação Proteica , Multimerização Proteica , TermodinâmicaRESUMO
The solvatochromic shift, as well as the change in colour of the simple organic dye nile red, is studied in two polar and two non-polar solvents in the context of large-scale time-dependent density-functional theory (TDDFT) calculations treating large parts of the solvent environment from first principles. We show that an explicit solvent representation is vital to resolve absorption peak shifts between nile red in n-hexane and toluene, as well as acetone and ethanol. The origin of the failure of implicit solvent models for these solvents is identified as being due to the strong solute-solvent interactions in form of π-stacking and hydrogen bonding in the case of toluene and ethanol. We furthermore demonstrate that the failures of the computationally inexpensive Perdew-Burke-Ernzerhof (PBE) functional in describing some features of the excited state potential energy surface of the S1 state of nile red can be corrected for in a straightforward fashion, relying only on a small number of calculations making use of more sophisticated range-separated hybrid functionals. The resulting solvatochromic shifts and predicted colours are in excellent agreement with experiment, showing the computational approach outlined in this work to yield very robust predictions of optical properties of dyes in solution.
RESUMO
We show that the transition origins of electronic excitations identified by quantified natural transition orbital (QNTO) analysis can be employed to connect potential energy surfaces (PESs) according to their character across a wide range of molecular geometries. This is achieved by locating the switching of transition origins of adiabatic potential surfaces as the geometry changes. The transition vectors for analysing transition origins are provided by linear response time-dependent density functional theory (TDDFT) calculations under the Tamm-Dancoff approximation. We study the photochemical CO ring opening of oxirane as an example and show that the results corroborate the traditional Gomer-Noyes mechanism derived experimentally. The knowledge of specific states for the reaction also agrees well with that given by previous theoretical work using TDDFT surface-hopping dynamics that was validated by high-quality quantum Monte Carlo calculations. We also show that QNTO can be useful for considerably larger and more complex systems: by projecting the excitations to those of a reference oxirane molecule, the approach is able to identify and analyse specific excitations of a trans-2,3-diphenyloxirane molecule.
RESUMO
We present a solution of the full time-dependent density-functional theory (TDDFT) eigenvalue equation in the linear response formalism exhibiting a linear-scaling computational complexity with system size, without relying on the simplifying Tamm-Dancoff approximation (TDA). The implementation relies on representing the occupied and unoccupied subspaces with two different sets of in situ optimised localised functions, yielding a very compact and efficient representation of the transition density matrix of the excitation with the accuracy associated with a systematic basis set. The TDDFT eigenvalue equation is solved using a preconditioned conjugate gradient algorithm that is very memory-efficient. The algorithm is validated on a small test molecule and a good agreement with results obtained from standard quantum chemistry packages is found, with the preconditioner yielding a significant improvement in convergence rates. The method developed in this work is then used to reproduce experimental results of the absorption spectrum of bacteriochlorophyll in an organic solvent, where it is demonstrated that the TDA fails to reproduce the main features of the low energy spectrum, while the full TDDFT equation yields results in good qualitative agreement with experimental data. Furthermore, the need for explicitly including parts of the solvent into the TDDFT calculations is highlighted, making the treatment of large system sizes necessary that are well within reach of the capabilities of the algorithm introduced here. Finally, the linear-scaling properties of the algorithm are demonstrated by computing the lowest excitation energy of bacteriochlorophyll in solution. The largest systems considered in this work are of the same order of magnitude as a variety of widely studied pigment-protein complexes, opening up the possibility of studying their properties without having to resort to any semiclassical approximations to parts of the protein environment.
RESUMO
We present calculations of formation energies of defects in an ionic solid (Al(2)O(3)) extrapolated to the dilute limit, corresponding to a simulation cell of infinite size. The large-scale calculations required for this extrapolation are enabled by developments in the approach to parallel sparse matrix algebra operations, which are central to linear-scaling density-functional theory calculations. The computational cost of manipulating sparse matrices, whose sizes are determined by the large number of basis functions present, is greatly improved with this new approach. We present details of the sparse algebra scheme implemented in the ONETEP code using hierarchical sparsity patterns, and demonstrate its use in calculations on a wide range of systems, involving thousands of atoms on hundreds to thousands of parallel processes.
RESUMO
A new framework is presented for evaluating the performance of self-consistent field methods in Kohn-Sham density functional theory (DFT). The aims of this work are two-fold. First, we explore the properties of Kohn-Sham DFT as it pertains to the convergence of self-consistent field iterations. Sources of inefficiencies and instabilities are identified, and methods to mitigate these difficulties are discussed. Second, we introduce a framework to assess the relative utility of algorithms in the present context, comprising a representative benchmark suite of over fifty Kohn-Sham simulation inputs, the scf-x n suite. This provides a new tool to develop, evaluate and compare new algorithms in a fair, well-defined and transparent manner.
RESUMO
In this work we study the solvatochromic shift of a selected low-energy excited state of alizarin in water by using a linear-scaling implementation of large-scale time-dependent density functional theory (TDDFT). While alizarin, a small organic dye, is chosen as a simple example of solute-solvent interactions, the findings presented here have wider ramifications for the realistic modeling of dyes, paints, and pigment-protein complexes. We find that about 380 molecules of explicit water need to be considered in order to yield an accurate representation of the solute-solvent interaction and a reliable solvatochromic shift. By using a novel method of constraining the TDDFT excitation vector, we confirm that the origin of the slow convergence of the solvatochromic shift with system size is due to two different effects. The first factor is a strong redshift of the excitation due to an explicit delocalization of a small fraction of the electron and the hole from the alizarin onto the water, which is mainly confined to within a distance of 7 Å from the alizarin molecule. The second factor can be identified as long-range electrostatic influences of water molecules beyond the 7 Å region on the ground-state properties of alizarin. We also show that these electrostatic influences are not well reproduced by a QM/MM model, suggesting that full QM studies of relatively large systems may be necessary in order to obtain reliable results.
RESUMO
Experimental techniques for electron energy loss spectroscopy (EELS) combine high energy resolution with high spatial resolution. They are therefore powerful tools for investigating the local electronic structure of complex systems such as nanostructures, interfaces and even individual defects. Interpretation of experimental electron energy loss spectra is often challenging and can require theoretical modelling of candidate structures, which themselves may be large and complex, beyond the capabilities of traditional cubic-scaling density functional theory. In this work, we present functionality to compute electron energy loss spectra within the onetep linear-scaling density functional theory code. We first demonstrate that simulated spectra agree with those computed using conventional plane wave pseudopotential methods to a high degree of precision. The ability of onetep to tackle large problems is then exploited to investigate convergence of spectra with respect to supercell size. Finally, we apply the novel functionality to a study of the electron energy loss spectra of defects on the (1 0 1) surface of an anatase slab and determine concentrations of defects which might be experimentally detectable.
RESUMO
Outbreaks of legionnaires' disease (LD) in tourists visiting Italian and Spanish resorts have been recently reported. An unusual number of reports of LD in tourists visiting the US Virgin Islands prompted an investigation of risk factors for development of LD in this area. Twenty-seven cases of LD were identified between 1979 and 1982 through press reports, personal communication, the national LD surveillance system, a review of hospital records, and a mail survey. Twenty-four of 27 persons with the disease had visited St Croix and 12 of them had stayed at a single hotel in 1981. Available evidence suggested that infection was due to Legionella pneumophila serogroup 1; L pneumophila serogroups 1 and 3 and several new Legionella species were isolated from the potable water system at the hotel. Following hyperchlorination of the potable water system, no further cases of LD in hotel visitors have been identified to date.
Assuntos
Surtos de Doenças/epidemiologia , Doença dos Legionários/epidemiologia , Viagem , Surtos de Doenças/diagnóstico , Feminino , Humanos , Legionella/isolamento & purificação , Doença dos Legionários/diagnóstico , Masculino , Pessoa de Meia-Idade , Vigilância da População , Estações do Ano , Testes Sorológicos , Inquéritos e Questionários , Ilhas Virgens AmericanasRESUMO
In a recently introduced rodent model of nicotine abstinence syndrome, the observed signs closely resembled those typical of rat opiate abstinence syndrome. Signs were precipitated by naloxone and potently reversed by morphine as well as nicotine itself, suggesting that nicotine might relieve nicotine abstinence syndrome through releasing endogenous opioids. To test this hypothesis, rats were continuously infused subcutaneously (SC) for 7 days with 9 mg/kg per day nicotine tartrate. Each rat was observed for abstinence signs at 18 and 21 h after termination of infusion. Three minutes before the 21-h test, all rats received 0.35 mg/kg nicotine tartrate, SC; 5 min before the nicotine injection, subjects received 9 or 4.5 mg/kg naloxone or saline alone, SC. Abstinence reversal scores were calculated as signs at 21 h as a percentage of signs at 18 h. Naloxone prevented nicotine alleviation of nicotine abstinence in a dose-related manner. However, naloxone in the absence of a nicotine injection had no effect on abstinence severity in either highly dependent or moderately dependent rats (infused with 9 or 5 mg/kg per day nicotine tartrate, respectively). These results support the hypothesis that endogenous opioids play a role in nicotine dependence and abstinence.
Assuntos
Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Nicotina/antagonistas & inibidores , Agonistas Nicotínicos/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Masculino , Naloxona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Nicotina/efeitos adversos , Nicotina/uso terapêutico , Agonistas Nicotínicos/efeitos adversos , Ratos , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
We discuss the use of ab initio quantum mechanical methods in drug metabolism studies. These methods require only the positions and atomic numbers of the atoms to be specified and offer greater transferability than conventional molecular modeling techniques. This fact, coupled with the accuracy of our approach, permits 'computational experiments' to be performed, allowing details of reaction mechanisms to be understood. We review the application of these methods to the cytochrome P450 superfamily of enzymes. There is much interest in understanding the mechanisms of these enzymes due to their participation in a wide range of metabolic processes including drug activation/deactivation. We find that our methods accurately reproduce the low- to high-spin transition of the haem Fe on binding of a substrate. Furthermore, we identify a new mechanism for the suppression of this spin transition, namely the shortening of the bond between the Fe atom and the coordinated S atom of the cysteine axial ligand. These results indicate that ab initio molecular modeling may be usefully applied in the study of drug metabolism and that further study of intermediate states in the P450 reaction cycle would be beneficial, particularly those which are not accessible using conventional experimental approaches.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Preparações Farmacêuticas/metabolismo , Fenômenos Químicos , Físico-Química , Cristalização , Sistema Enzimático do Citocromo P-450/química , Heme/química , Heme/metabolismo , Humanos , Ferro/química , Modelos MolecularesRESUMO
In two experiments subjects judged the loudness of a 1000-Hz tone within a range of three loudnesses. The first used a within-subjects design with ranges of 1-2 sones, 1-4 sones, and 1-8 sones. The second used a between-subjects design with ranges of 1-2 sones, 1-8 sones, and 1-16 sones. Except for two values in the 1- to 2-sone range the two experiments produced comparable results. As range was increased the tendency to round away from the end points increased and the judged mid-point occurred at a higher value. Comparisons are made with rounding patterns that occur in studies of linear scales. The present results are interpreted to support Poulton's (1975) position, that the mid-point of subjective estimates depends on the range of stimuli judged, rather than that of Stevens (1975), that the mid-point on a prosthetic scale is assigned to a value that is lower than the mid-point on the subject's subjective scale.
Assuntos
Percepção Sonora , Estimulação Acústica , Humanos , PsicofísicaRESUMO
Effects of noise frequencies on both performance on a complex psychomotor task and annoyance were investigated for men (n = 30) and women (n = 30). Each subject performed a complex psychomotor task for 50 min. in the presence of low frequency noise, high frequency noise, or ambient noise. Women and men learned the task at different rates. Little effect of noise was shown. Annoyance ratings were subsequently obtained from each subject for noise of various frequencies by the method of magnitude estimation. High frequency noises were more annoying than low frequency noises regardless of sex and immediate prior exposure to noise. Sex differences in annoyance did not occur. Not direct relationship between learning to perform a complex task while exposed to noise and annoyance by that noise was demonstrated.