A simple Cα-SC potential with higher accuracy for protein fold recognition

In this paper, an improved C_α-SC energy potential designed for protein fold recognition was reported. It consists of three extremely simple interaction terms which are supposed to be the dominant interactions in protein folding: residue-residue contact, hydrophobicity and pseudodihedral potentials. The potential function only contains 210 contacts, one hydrophobic and one torsion parameters, which have been optimized using an interior point algorithm of linear programming. Tests of the derived potential function on commonly used decoy sets illustrate that it outperforms most of the existing coarse-grained potentials in terms of its capabilities in recognizing native structures and consistency in achieving high Z-scores across decoy sets, and it has almost equivalent performance to the potentials which considered complex intra-molecular interactions. The results show that our scoring function is a generally prospective potential for protein structure prediction and modeling with regard to its recognition and computation efficacy.     

Dissociation of Aun (n = 3, 4) Microclusters

Abstract

The dissociation of Au₃ and Au₄ microclusters has been investigated using a molecular-dynamics computer simulation. The potential energy function used in the calculations includes two- and three-body interactions, which are represented by Lennard-Jones and Axilrod-Teller potentials, respectively. It has been found that dissociation starts for both clusters after 3000K.     

The biomimetic [Cr3O(O2CCH2CH3)6(H2O)3]+ decreases plasma cholesterol and triglycerides in rats: towards chromium-containing therapeutics

3 O(O₂CCH₂CH₃)₆ (H₂O)₃]⁺ 1 and a naturally occurring, biologically active form of chromium, low-molecular-weight chromium-binding substance (LMWCr), to rats are described. Given that the complexes are proposed to function by interacting with insulin receptor, trapping it in its active conformation, in contrast to current chromium-containing nutrition supplements, which only serve as sources of absorbable chromium, changes in lipid and carbohydrate metabolism would be expected. After 12 weeks administration (20 μg/kg body mass), compound 1 results in 40% lower levels of blood plasma LDL cholesterol, 33% lower levels of total cholesterol, and significantly lower HDL cholesterol and triglyceride; these results are in stark contrast to those of administration of other forms of Cr(III) to rats, which have no effect on these parameters. LMWCr, in contrast to 1, has no effect as it probably is degraded in vivoor excreted. These results are interpreted in terms of the mechanism of chromium action in response to insulin and the activation of insulin receptor, and the potential for the rational design of chromium-containing therapeutics is discussed. Received: 27 May 1999 / Accepted: 4 October 1999     

Procognitive 5-HT6 antagonists in the rat forced swimming test: Potential therapeutic utility in mood disorders associated with Alzheimer's disease

Aims5-HT₆ receptor subtype is predominantly expressed in the brain, and preclinical evidence suggests its potential role in the cognitive function. Brain microdialysis studies demonstrated that 5-HT₆ antagonists enhance not only cholinergic but also monoaminergic neurotransmission, a property that may differentiate from acetylcholine esterase (AChE) inhibitors such as donepezil. In this study we compared the antidepressant-like effects of 5-HT₆ antagonists with donepezil to determine whether their different effects on monoamines are behaviorally relevant.Main methodsSelective 5-HT₆ antagonists (SB-399885 and SB-271046) and donepezil were evaluated in the rat forced swimming test since this is known to identify drugs such as antidepressants which can increase brain monoamine levels. Binding assay was undertaken by using [¹²⁵I]SB-258585 to measure brain 5-HT₆ receptor occupancy.Key findingsSystemic administration of SB-399885 (3 and 10 mg/kg, i.p.) and SB-271046 (10 and 30 mg/kg, i.p.) produced a significant reduction of immobility time in the rat forced swimming test with a similar profile in terms of 5-HT₆ receptor occupancy (62 and 96% for 3 and 10 mg/kg SB-399885 respectively; 56 and 84% for 10 and 30 mg/kg SB-271046 respectively). In contrast, donepezil (0.5 and 1 mg/kg i.p.) did not show any effects in this model.SignificanceThese data suggest that 5-HT₆ antagonists, at doses corresponding to those occupy central 5-HT₆ receptors, could have an antidepressive effect in humans. This may differentiate 5-HT₆ antagonists from AChE inhibitors with respect to the mood control in the symptomatic treatment of Alzheimer's disease.     

Brownian Dynamics Computer Simulations of Quenched Lennard-Jones-like Fluids: I Morphology and Local Structural Evolution

Abstract

The structural characteristics during phase separation of a model colloidal system were investigated using Brownian dynamics simulation. The structures that formed were analysed using the radial distribution function and structure factor in separate time periods after the quench. The data were interpreted in terms of scale-invariancy and density inhomogeneities. The systems, which consisted of a gas-like phase and dense liquid or solid-like regions, developed with a highly interconnected morphology during the simulations. The aggregate morphology was sensitive to the range of the attractive part of the potential and the position in the phase diagram after the quench. The long-range 12:6 potential induced compact structures with thick filaments, whereas the systems generated using the shorter-ranged 24:12 and 36:18 potentials persisted in a more diffuse network and also evolved more slowly with time. The fractal dimensions were quite high, typically close to 3. The 24:12 and 36:18 potential systems developed regions of local crystalline order which formed contemporaneously with the more global morphological changes. In contrast, at low temperatures the particles of the longer-range 12:6 potential became trapped in glass-like states during the course of the morphological changes in the system. The value of the characteristic lengthscale with time exponent, α, was found to be dependent on the temperature, density and interaction potential and therefore cannot be described as ‘universal’.     

Genetic and physiological evidence concerning the development of chemically sensitive voltage-dependent ionophores in L6 cells

The electrophysiological properties of a tissue culture muscle line, L₆, and a K⁺ resistant mutant (MK₁) derived from L₆ were determined to elucidate certain aspects of membrane differentiation and function. MK₁ was selected as a clone of myoblasts resistant to the toxic effects of 55 mM K⁺. The resting potentials of L₆ and MK₁ myoblasts and myotubes were K⁺ dependent and equal. The amplitudes of the action potentials were equal in normal medium, but 27.7 mM K⁺ interfered with or eliminated the ability of L₆ myotubes to produce action potentials. MK₁ myotubes produced nearly normal action potentials under these conditions. Thus, the K⁺ resistant myoblasts differentiate into myotubes which have an action potential generating mechanism much less sensitive to K⁺ than the normal mechanism. Also, both d-tubocurarine and α-bungarotoxin enhance the amplitude of the action potentials produced by L₆ myotubes in the presence of 27.7 mM K⁺; these compounds do not enhance the amplitude of the action potentials produced by MK₁ myotubes under the same conditions. It is proposed that as a consequence of differentiation a type of ionophore present in myoblasts becomes a voltage-dependent ionophore in myotubes. Furthermore, these voltage-dependent ionophores can be chemically sensitive.     

疏风解毒胶囊辅以综合管理干预对慢性阻塞性肺疾病患者呼吸及运动功能的影响

摘要 目的：探讨疏风解毒胶囊辅以综合管理干预对慢性阻塞性肺疾病（COPD）患者呼吸及运动功能改善的影响。方法：选取2018年10月-2019年10月到我院进行治疗的COPD患者84例作为研究对象,随机数字表法分为两组,患者均使用疏风解毒胶囊进行治疗,对照组（n=42）予以常规干预,试验组（n=42）进行综合管理干预。对比两组患者的临床治疗有效率、肺功能改善情况、肺功能指标、呼吸困难指数（MRC）评分以及6分钟步行实验（6MWT）结果。结果：试验组的临床治疗有效率高于对照组（P<0.05）。干预后,两组动脉血二氧化碳分压（PaCO₂）和MRC评分较干预前降低（P<0.05）,动脉血氧分压（PaO₂）、动脉血氧饱和度（SaO₂）、第1秒用力呼气容器（FEV₁）、用力肺活量（FVC）、FEV₁/FVC均较干预前升高（P<0.05）,6MWT距离较干预前增加（P<0.05）,且试验组上述指标改善情况更优（P<0.05）。结论：疏风解毒胶囊辅以综合管理干预可提高COPD患者的临床治疗效果,改善其肺功能,可有效缓解呼吸困难,提升运动强度,值得在临床上应用与推广。     

Anisotropic Site-Site Potentials in Molecular Dynamics

Abstract

This paper describes techniques for calculating the forces and torques for molecular simulations that use anisotropic site-site potentials. The general techniques are illustrated for pairs of linear and tetrahedral molecules. A technique for combining anisotropic site-site potentials with constraint dynamics is described. These ideas are tested by simulating an anisotropic site-site potential model for the non-bonded interactions in liquid butane. This model is as accurate as the all-atom Williams potential from which it is derived but can be simulated using approximately half the computer time of the all-atom potential. Anisotropic site-site potentials offer a flexible and cost-effective method of simulating a range of hydrocarbon systems.     

Contents to volume 164

Cytochrome b₆ from spinach chloroplasts (either within the purified cytochrome b₆f complex, or in its isolated form) exhibits two spectral species, which correspond to two midpoint potentials. This can be demonstrated by low temperature difference spectroscopy at fixed redox potentials. The high potential form of cytochrome b₆ has a split α-peak at 557.5 and 561.5 nm, the low potential form has a symmetrical α-peak at 560.5 nm. Similar results were obtained with cytochrome b₆ in the isolated cytochrome b₆f complex from the cyanobacterium Anabaena variabilis.     

Pacemaker Potentials for the Periodic Burst Discharge in the Heart Ganglion of a Stomatopod, Squilla oratoria

From somata of the pacemaker neurons in the Squilla heart ganglion, pacemaker potentials for the spontaneous periodic burst discharge are recorded with intracellular electrodes. The electrical activity is composed of slow potentials and superimposed spikes, and is divided into four types, which are: (a) "mammalian heart" type, (b) "slow generator" type, (c) "slow grower" type, and (d) "slow deficient" type. Since axons which are far from the somata do not produce slow potentials, the soma and dendrites must be where the slow potentials are generated. Hyperpolarization impedes generation of the slow potential, showing that it is an electrically excitable response. Membrane impedance increases on depolarization. Brief hyperpolarizing current can abolish the plateau but brief tetanic inhibitory fiber stimulation is more effective for the abolition. A single stimulus to the axon evokes the slow potential when the stimulus is applied some time after a previous burst. Repetitive stimuli to the axon are more effective in eliciting the slow potential, but the depolarization is not maintained on continuous stimulation. Synchronization of the slow potential among neurons is achieved by: (a) the electrotonic connections, with periodic change in resistance of the soma membrane, (b) active spread of the slow potential, and (c) synchronization through spikes.     

On the mechanism of cesium-induced voltage and current tails in single ventricular myocytes

The mechanisms by which different concentrations of cesium modify membrane potentials and currents were investigated in guinea pig single ventricular myocytes. In a dose-dependent manner, cesium reversibly decreases the resting potential and action potential amplitude and duration, and induces a diastolic decaying voltage tail (V_ex), which increases at more negative and reverses at less negative potentials. In voltage-clamped myocytes, Cs⁺ increases the holding current, increases the outward current at plateau levels while decreasing it at potentials closer to resting potential, induces an inward tail current (I_ex) on return to resting potential and causes a negative shift of the threshold for the inward current. During depolarizing ramps, Cs⁺ decreases the outward current negative to inward rectification range, whereas it increases the current past that range. During repolarizing ramps, Cs⁺ shifts the threshold for removal of inward rectification negative slope to less negative values. Cs⁺-induced voltage and current tails are increased by repetitive activity, caffeine (5 mM) and high [Ca²⁺]_o (8.1 mM), and are reduced by low Ca²⁺ (0.45 mM), Cd²⁺ (0.2 mM) and Ni²⁺ (2 mM). Ni²⁺ also abolishes the tail current that follows steps more positive than E_Ca. We conclude that Cs⁺ (1) decreases the resting potential by decreasing the outward current at more negative potentials, (2) shortens the action potential by increasing the outward current at potentials positive to the negative slope of inward rectification, and (3) induces diastolic tails through a Ca²⁺-dependent mechanism, which apparently is an enhanced electrogenic Na-Ca exchange.     

Ab initio study of phenyl benzoate: structure,conformational analysis,dipole moment,IR and Raman vibrational spectra

The molecular structure (bond distances and angles), conformational properties, dipole moment and vibrational spectroscopic data (vibrational frequencies, IR and Raman intensities) of phenyl benzoate were calculated using Hartree–Fock (HF), density functional (DFT), and second order Møller–Plesset perturbation theory (MP2) with basis sets ranging from 6-31G* to 6-311++G**. The theoretical results are discussed mainly in terms of comparisons with available experimental data. For geometric data, good agreement between theory and experiment is obtained for the MP2, B3LYP and B3PW91 levels with basis sets including diffuse functions. The B3LYP/6-31+G* theory level estimates the shape of the experimental functions for phenyl torsion around the Ph–O and Ph–C bonds well, but reproduces the height of the rotational barriers poorly. The B3LYP/6-31+G* harmonic force constants were scaled by applying the scaled quantum mechanical force field (SQM) technique. The calculated vibrational spectra were interpreted and band assignments were reported. They are in excellent agreement with experimental IR and Raman spectra.Figure Calculated and experimental (GED) potential energy functions for torsional motion of phenyl benzoate relative to the minimum value. a The potential function for torsion about the O₃–C₄ bond. b The potential function for torsion about the C₂–C₁₀ bond.     

Hesperidin depolarizes the pacemaker potentials through 5-HT4 receptor in murine small intestinal interstitial cells of Cajal

ABSTRACT

Hesperidin, a citrus flavonoid, can exert numerous beneficial effects on human health. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract. In the present study, we investigated potential effects of hesperidin on pacemaker potential of ICC in murine small intestine and GI motility. A whole-cell patch-clamp configuration was used to record pacemaker potential in ICC, and GI motility was investigated in vivo by recording gastric emptying (GE) and intestinal transit rate (ITR). Hesperidin depolarized pacemaker potentials of ICC in a dose-dependent manner. Pre-treatment with methoctramine or 4-DAMP did not inhibit hesperidin-induced pacemaker potential depolarization. Neither a 5-HT₃ receptor antagonist (Y25130) nor a 5-HT₇ receptor antagonist (SB269970) reduced the effect of hesperidin on ICC pacemaker potential, whereas the 5-HT₄ receptor antagonist RS39604 was found to inhibit this effect. In the presence of GDP–β–S, hesperidin-induced pacemaker potential depolarization was inhibited. Moreover, in the presence of U73122 and calphostin C, hesperidin did not depolarize pacemaker potentials. Furthermore, hesperidin accelerated GE and ITR in vivo. These results imply that hesperidin depolarized ICC pacemaker potential via 5-HT₄ receptors, G protein, and PLC/PKC dependent pathways and that it increased GI motility. Therefore, hesperidin may be a promising novel drug to regulate GI motility.     

Comparative analysis of surface electrostatic potentials of carbon, boron/nitrogen and carbon/boron/nitrogen model nanotubes

We have extended an earlier study, in which we characterized in detail the electrostatic potentials on the inner and outer surfaces of a group of carbon and B_xN_x model nanotubes, to include several additional ones with smaller diameters plus a new category, C_2xB_xN_x. The statistical features of the surface potentials are presented and analyzed for a total of 19 tubes as well as fullerene and a small model graphene. The potentials on the surfaces of the carbon systems are relatively weak and rather bland; they are much stronger and more variable for the B_xN_x and C_2xB_xN_x. A qualitative correlation with free energies of solvation indicates that the latter two categories should have considerably greater water solubilities. The inner surfaces are generally more positive than the corresponding outer ones, while both positive and negative potentials are strengthened by increasing curvature. The outsides of B_xN_x tubes have characteristic patterns of alternating positive and negative regions, while the insides are strongly positive. In the closed C_2xB_xN_x systems, half of the C–C bonds are double-bond-like and have negative potentials above them; the adjacent rows of boron and nitrogens show the usual B_xN_x pattern. When the C_2xB_xN_x tubes are open, with hydrogens at the ends, the surface potentials are dominated by the B⁺–H^– and N^––H⁺ linkages.Figure Calculated electrostatic potential on the molecular surface of closed (6,0) B₄₈N₄₈; a is an outside view, while b shows the interior. Color ranges, in kcal mol^–1: red, greater than 20; yellow, between 20 and 0; green, between 0 and –10; blue, between –10 and –20; purple, more negative than –20     

Logical analysis of the mechanism of protein folding III. Prediction of the strong long-range interactions.

It has been found that strong long-range interactions occur in regions having large β-structural potentials. As has been described previously (Nagano, 1974), interactions among regions having both helical and β-structural potentials (αβ-gaβ interactions) are also very important. Accordingly, an idea is presented in this paper that the relative stability of a protein conformation could be estimated by a relatively simple mathematical function of sequence and conformation. The function P(p,q) is called the non-energy part of pseudo-free energy, because minimization of the sum of P(p,q) and energy functions (cf. Levitt, 1974; Warme &; Scheraga, 1974) can be expected to lead to a plausible model of a protein. A merit of the function is that it can help us decide which way to go in manipulating a temporarily built model, e.g. towards a helix-rich protein or towards a β-structure-rich protein. The estimation of P(p,q) as an artificial potential does not use much computer time because only the co-ordinates of the β-carbon atoms (α-carbon atoms if the residue is Gly) are used. It is composed of terms of the long-range interactions P_L and short-range interactions P_S. The term P_L represents the relative strength of helix-helix interactions, helix-β-candidate interactions and β-candidate-β-candidate interactions. It is assumed that both helical and β-structural potentials can be measured as the differences between the predicted function for helix and β-structure, respectively, as defined previously (Nagano, 1973), and the corresponding largest values ever found. A hypothesis that two residues distantly separated in the primary sequence contribute less to the stability of the whole molecule is finally discarded because the true conformation of concanavalin A becomes very unstable compared with its false conformation folded like the main part of subtilisin. The parameters thus determined indicate that the helix-β-candidate interactions are almost as important as the β-candidate-β-candidate interactions. Both helix and loop prediction functions are combined to give the short-range interactions term, P_S, according to whether the region is really helical or not, and to whether it is really looped or not. The function P(p,q) can be used as a criterion for judging whether the predicted conformation is realistic or false, because the parameters can be adjusted to give, within limits, reasonable values of −10 kcal/residue for true conformations and higher than −5 kcal/residue for false conformations.As an application of the present theory of protein folding, the tertiary structure of bacteriophage T4 lysozyme is predicted and presented in Figure 1, prior to the X-ray structure becoming available.     

On Multiple Time-step Algorithms and the Ewald Sum

Abstract

We show how standard multiple time-step algorithms devised for systems with short-range potentials can be used successfully in simulations of periodic systems with long-range (Coulombic) potentials. Three strategies for incorporating the Ewald sum into a multiple time-step algorithm are considered. These are (i) evaluation of reciprocal space terms every time-step (ii) evaluating reciprocal space terms once every n time-steps and placing these terms in with the slowly varying forces and energies (iii) a modified form of the second strategy in which primary shell (close) electrostatic interactions are evaluated directly and the more distant interactions handled by the Ewald sum (once every n time-steps). Only the first and third approaches give satisfactory thermodynamic results. The third strategy is much more efficient than the first. With the third strategy substantial savings in cpu time are acheived in both the real space and, most importantly, the reciprocal space terms of the Ewald sum. This is achieved without significant loss of accuracy or stability. Overall execution time is decreased by a factor of between 2 and 3.     

One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a–p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC₅₀ =?6.70, 6.40 and 6.70?µM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC₅₀ =?120 and 150?nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.     

Sodium conductance kinetics

Methods are described for extracting the rate constants, governing the transitions between states, for a generalized, linear three discrete state model for the Na conductance,g _Na. It is shown that the problem cannot be solved given only the time course ofg _Na during some test potential step with fixed initial conditions. However, if the effects of any two durations of some conditioning potential step on the peakg _Na during the test step are taken into account, and the physically required assumption that the steady state is an equilibrium state is made, then the rate constants for both conditioning and test potentials can be solved for simultaneously. These methods were applied to thev ⁵ model of Goldman (5) in which theg _Na(t) was described in terms of a generalized linear second order variable. After extensive computations involving some 20,000 combinations of experimentally determined input values, it was not found possible to extract a set of rate constants that were all real and positive as is required. It was concluded that if the transitions between states are first order and there are no subunit interactions, then the Na gating unit displays more than three states.     

Neuron as time coherence discriminator

Neuronal excitability under stimuli with a complex time course is investigated on the basis of the numerical solution of the Hodgkin-Huxley equations. Each stimulus is composed of 100–1000 unitary excitatory postsynaptic potentials (uEPSP) that start randomly within a definite time window. Probability of initiating a spike [firing probability, FP(W)] as a function of the window width W is calculated by the Monte Carlo method. FP(W) has a step-like shape: it becomes equal to 1 for small W and almost vanishes as W exceeds some value W _S. The role of long-lasting somatic inhibition is analysed. W _S depends on the inhibition potential, but the step-like shape of FP is preserved. It is concluded that the capability of multisynaptic stimulation to cause a spike can be expressed in terms of temporal coherence between the synaptic inputs. Namely, the spike is initiated if the temporal coherence between active inputs is above a definite threshold. The threshold value can be effectively regulated by varying the inhibition potential.