scholarly journals General structure-free energy relationships of hERG blocker binding under native cellular conditions

2021 ◽  
Author(s):  
Hongbin Wan ◽  
Kristina Spiru ◽  
Sarah Williams ◽  
Robert Alan Pearlstein
Keyword(s):  
Free Energy ◽  
Potassium Channel ◽  
General Structure ◽  
Second Order ◽  
Related Gene ◽  
Order Entry ◽  
First Order ◽  
Energy Relationships ◽  
Bond Network ◽  
Dissociation Barrier

We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water ('the solvation field') relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We analyzed blockade of the ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as 'BP') into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as 'BC') occupying the cytoplasmic 'antechamber' of hERG; and 2) undergo second-order entry to the antechamber, followed by first-order association of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polar pore is solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereas blocker BP moieties are solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, the blocker solvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with blocker potency and Redfern safety classification.

Effect of Preferential Solvation on the Kinetics and Thermodynamics of Oxidation of Anilines by Nicotinium Dichromate

2005 ◽  
Vol 60 (10) ◽  
pp. 1105-1111 ◽  
Author(s):  
Durvas S. Bhuvaneshwari ◽  
Kuppanagounder P. Elango
Keyword(s):  
Free Energy ◽  
Preferential Solvation ◽  
Zero Order ◽  
Substituted Anilines ◽  
Isokinetic Relationship ◽  
Solvent Interactions ◽  
Activation Free Energy ◽  
First Order ◽  
Linear Free Energy ◽  
Energy Relationships

The nicotinium dichromate (NDC) oxidation of anilines, in varying mole fractions of benzene/2- methylpropan-2-ol mixtures, in the presence of p-toluenesulfonic acid (TsOH) is first order in NDC and TsOH and zero order with respect to anilines in the concentration range investigated. The NDC oxidation of 15 meta- and para-substituted anilines complies with the isokinetic relationship but not to any of the linear free energy relationships. The activation free energy data failed to correlate with macroscopic solvent parameters such as εr and ENT. Correlation of ΔG# with Kamlet-Taft solvatochromic parameters (α, β , π*) suggests that the specific solute-solvent-solvent interactions play a major role in governing the reactivity.

Perturbation Theory and the Triangular Well Potential

1975 ◽  
Vol 53 (1) ◽  
pp. 5-12 ◽  
Author(s):  
W. R. Smith ◽  
D. Henderson ◽  
J. A. Barker
Keyword(s):  
Free Energy ◽  
Distribution Function ◽  
Perturbation Theory ◽  
Radial Distribution Function ◽  
Radial Distribution ◽  
Order Term ◽  
Second Order ◽  
First Order ◽  
Triangular Well Potential

Accurate calculations of the second order term in the free energy and the first order term in the radial distribution function in the Barker–Henderson (BH) perturbation theory are presented for the triangular well potential. The BH theory is found to be fully satisfactory for this system. Thus, the conclusions of Card and Walkley regarding the accuracy of the BH theory are erroneous.

SECOND ORDER HIGH DENSITY EXPANSION FOR FREE ENERGY AND ORDER PARAMETER

1991 ◽  
Vol 05 (18) ◽  
pp. 2935-2949
Author(s):  
M. BARTKOWIAK ◽  
K.A. CHAO
Keyword(s):  
Free Energy ◽  
Order Parameter ◽  
Order Approximation ◽  
Local Approximation ◽  
Second Order ◽  
High Density ◽  
First Order ◽  
First Order Approximation ◽  
Consistent Equation ◽  
Density Expansion

The self-consistently renormalized high-density expansion (SHDE) is first used to determine temperature dependence of order parameter. Free energy and magnetization of the Ising model has been calculated to the second order. It is shown that the unphysical discontinuity of the order parameter as a function of temperature, which appears in the first-order approximation, still remains in the second-order calculation. Based on the 1/d expansion, we then construct a method to select (1/z)i contributions from the high density expansion terms. This method is applied to the first and second-order self-consistent equation for magnetization. Selection of the first order in 1/z contributions within the first order of the SHDE leads to considerable improvement of the behavior of magnetization as a function of temperature, and application of the local approximation to the second order of the SHDE term gives an acceptable single-value behavior of the order parameter.

scholarly journals ON THE ALL ORDER SOLUTIONS OF SEIBERG-WITTEN MAP FOR NONCOMMUTATIVE GAUGE THEORIES

2012 ◽  
Vol 13 ◽  
pp. 191-198 ◽  
Author(s):  
KAYHAN ÜLKER
Keyword(s):  
Gauge Theories ◽  
General Structure ◽  
Homogeneous Solution ◽  
Second Order ◽  
Homogeneous Solutions ◽  
First Order ◽  
Noncommutative Gauge Theories ◽  
Recursive Solutions

We review the recursive solutions of the Seiberg–Witten map to all orders in θ for gauge, matter and ghost fields. We also present the general structure of the homogeneous solutions of the defining equations. Moreover, we show that the contribution of the first order homogeneous solution to the second order can be written recursively similar to inhomogeneous solutions.

The magnetic transition in moderately small superconductors, and the influence of elastic strain

1975 ◽  
Vol 278 (1282) ◽  
pp. 311-341 ◽  
Keyword(s):  
Phase Diagram ◽  
Free Energy ◽  
Thermodynamic Equilibrium ◽  
Elastic Strain ◽  
Energy Difference ◽  
Second Order ◽  
Field Energy ◽  
First Order ◽  
Independent Term ◽  
Field Independent

Measurements have been made of the onset of the superconducting phase transition of tin whiskers (single crystals of diameter 1—2 μm and length several millimetres) as a function of temperature T , magnetic field H , and elastic strain ε up to 2%. For samples of this size (denoted ‘moderately small ’ since they are larger than λ(0)), there is a range of temperatures, approximately 20-30 mK below the transition temperature T e (ε), for which the transition is of second order in the Ehrenfest sense. Below the temperature denoted T ' (ε) the transition is of first order and may exhibit hysteresis. The phase diagram at constant strain is derived from the equation Δ G = − A ψ 2 + 1 2 B ψ 4 + 1 3 C ψ 6 , where Δ G is the free energy difference between the superconducting and normal states, ψ is the wave function of the superconducting electrons, and the coefficients A , B and C each comprise two terms, of which one is field-dependent, being proportional to H 2 . The other, field-independent, term is Ginzburg’s (1958) expression for the zero-field energy difference, so that A contains a term proportional to ( T c — T ), and B is independent of T . Coefficient C contains a field-independent term, assumed independent of T , which we introduce for consistency. The condition A = 0 describes both the secondorder transition and limiting supercooling, while the transition at thermodynamic equilibrium in the first order region and limiting superheating are described by B 2 = − 16 3 A C and B 2 = — 4 AC respectively. The Landau critical point ( H ', T ') is given by B — 0, A = 0. If the limiting metastable transitions for a cylinder in parallel field are included on a phase diagram, then the supercooling curve is a continuation of the second order curve while the curve for thermodynamic equilibrium branches from it tangentially if C ( H ', T ') > 0, or at a slope which is 1.32 times greater than this if C ( H ', T ’) = 0. The case C ( H ', T ') < 0 is discussed elsewhere (Nabarro & Bibby 1974, following paper in this volume). The last case arises because our observations indicate that the field-independent term in C is negative. Estimates of the sample size were made by using the present theory and were in fair agreement with estimates made electron-microscopically. Expressions for the change at the superconducting transition of the specific heat and other second derivatives of the Gibbs free energy above and below T ' are derived. It is shown theoretically that the transition remains of second order when the sample is strained elastically. Some of the Ehrenfest relations describing a second order transition with two independent variables are experimentally verified from our data.

Nonlinear Analysis of Visual Evoked Potentials Elicited by Color Stimulation

1997 ◽  
Vol 36 (04/05) ◽  
pp. 315-318 ◽  
Author(s):  
K. Momose ◽  
K. Komiya ◽  
A. Uchiyama
Keyword(s):  
Visual System ◽  
Evoked Potentials ◽  
Visual Evoked Potentials ◽  
Normal Subjects ◽  
Second Order ◽  
First Order ◽  
The Relationship ◽  
Perceived Color ◽  
Second Order Nonlinearity ◽  
Visual Evoked

Abstract:The relationship between chromatically modulated stimuli and visual evoked potentials (VEPs) was considered. VEPs of normal subjects elicited by chromatically modulated stimuli were measured under several color adaptations, and their binary kernels were estimated. Up to the second-order, binary kernels obtained from VEPs were so characteristic that the VEP-chromatic modulation system showed second-order nonlinearity. First-order binary kernels depended on the color of the stimulus and adaptation, whereas second-order kernels showed almost no difference. This result indicates that the waveforms of first-order binary kernels reflect perceived color (hue). This supports the suggestion that kernels of VEPs include color responses, and could be used as a probe with which to examine the color visual system.

Imaginings

2017 ◽  
Vol 9 (3) ◽  
pp. 17-30
Author(s):  
Kelly James Clark
Keyword(s):  
Religious Tradition ◽  
Second Order ◽  
Fine Tuning ◽  
Intellectual Humility ◽  
First Order ◽  
Natural Processes ◽  
Empirically Supported ◽  
Group Violence ◽  
The World ◽  
The Universe

In Branden Thornhill-Miller and Peter Millican’s challenging and provocative essay, we hear a considerably longer, more scholarly and less melodic rendition of John Lennon’s catchy tune—without religion, or at least without first-order supernaturalisms (the kinds of religion we find in the world), there’d be significantly less intra-group violence. First-order supernaturalist beliefs, as defined by Thornhill-Miller and Peter Millican (hereafter M&M), are “beliefs that claim unique authority for some particular religious tradition in preference to all others” (3). According to M&M, first-order supernaturalist beliefs are exclusivist, dogmatic, empirically unsupported, and irrational. Moreover, again according to M&M, we have perfectly natural explanations of the causes that underlie such beliefs (they seem to conceive of such natural explanations as debunking explanations). They then make a case for second-order supernaturalism, “which maintains that the universe in general, and the religious sensitivities of humanity in particular, have been formed by supernatural powers working through natural processes” (3). Second-order supernaturalism is a kind of theism, more closely akin to deism than, say, Christianity or Buddhism. It is, as such, universal (according to contemporary psychology of religion), empirically supported (according to philosophy in the form of the Fine-Tuning Argument), and beneficial (and so justified pragmatically). With respect to its pragmatic value, second-order supernaturalism, according to M&M, gets the good(s) of religion (cooperation, trust, etc) without its bad(s) (conflict and violence). Second-order supernaturalism is thus rational (and possibly true) and inconducive to violence. In this paper, I will examine just one small but important part of M&M’s argument: the claim that (first-order) religion is a primary motivator of violence and that its elimination would eliminate or curtail a great deal of violence in the world. Imagine, they say, no religion, too.Janusz Salamon offers a friendly extension or clarification of M&M’s second-order theism, one that I think, with emendations, has promise. He argues that the core of first-order religions, the belief that Ultimate Reality is the Ultimate Good (agatheism), is rational (agreeing that their particular claims are not) and, if widely conceded and endorsed by adherents of first-order religions, would reduce conflict in the world.While I favor the virtue of intellectual humility endorsed in both papers, I will argue contra M&M that (a) belief in first-order religion is not a primary motivator of conflict and violence (and so eliminating first-order religion won’t reduce violence). Second, partly contra Salamon, who I think is half right (but not half wrong), I will argue that (b) the religious resources for compassion can and should come from within both the particular (often exclusivist) and the universal (agatheistic) aspects of religious beliefs. Finally, I will argue that (c) both are guilty, as I am, of the philosopher’s obsession with belief. 

Hydrogen Atom Transfer Reaction Free Energy as a Predictor of Abiotic Nitroaromatic Reduction Rate Constants: A Comprehensive Analysis

2019 ◽  
Author(s):  
Dominic Di Toro ◽  
Kevin P. Hickey ◽  
Herbert E. Allen ◽  
Richard F. Carbonaro ◽  
Pei C. Chiu
Keyword(s):  
Free Energy ◽  
Hydrogen Atom ◽  
Hydrogen Atom Transfer ◽  
Energy Model ◽  
Second Order ◽  
Transfer Model ◽  
Atom Transfer ◽  
Order Rate ◽  
Linear Free Energy ◽  
Free Energy Model

<div>A linear free energy model is presented that predicts the second order rate constant for the abiotic reduction of nitroaromatic compounds (NACs). For this situation previously presented models use the one electron reduction potential of the NAC reaction. If such value is not available, it has been has been proposed that it could be computed directly or estimated from the electron affinity (EA). The model proposed herein uses the Gibbs free energy of the hydrogen atom transfer (HAT) as the parameter in the linear free energy model. Both models employ quantum chemical computations for the required thermodynamic parameters. The available and proposed models are compared using second order rate constants obtained from five investigations reported in the literature in which a variety of NACs were exposed to a variety of reductants. A comprehensive analysis utilizing all the NACs and reductants demonstrate that the computed hydrogen atom transfer model and the experimental one electron reduction potential model have similar root mean square errors and residual error probability distributions. In contrast, the model using the computed electron affinity has a more variable residual error distribution with a significant number of outliers. The results suggest that a linear free energy model utilizing computed hydrogen transfer reaction free energy produces a more reliable prediction of the NAC abiotic reduction second order rate constant than previously available methods. The advantages of the proposed hydrogen atom transfer model and its mechanistic implications are discussed as well.</div>

How to Fluorescently Label the Potassium Channel: A Case in hERG

2020 ◽  
Vol 27 (18) ◽  
pp. 3046-3054
Author(s):  
Xiaomeng Zhang ◽  
Beilei Wang ◽  
Zhenzhen Liu ◽  
Yubin Zhou ◽  
Lupei Du
Keyword(s):  
Potassium Channel ◽  
Herg Channel ◽  
Pore Channel ◽  
Design Rationale ◽  
Related Gene ◽  
Open Conformation ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Herg Channels ◽  
Action Potential Repolarization

hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.

Evidence for general base catalysis by protic solvents in a kinetic study of alcoholyses and hydrolyses of 1-(phenoxycarbonyl)pyridinium ions under both solvolytic and non-solvolytic conditions

2009 ◽  
Vol 74 (1) ◽  
pp. 43-55 ◽  
Author(s):  
Dennis N. Kevill ◽  
Byoung-Chun Park ◽  
Jin Burm Kyong
Keyword(s):  
Second Order ◽  
Base Catalysis ◽  
Substitution Reactions ◽  
Third Order ◽  
Methoxy Derivative ◽  
First Order ◽  
General Base ◽  
Protic Solvents ◽  
Kinetics Of ◽  
Pyridinium Ions

The kinetics of nucleophilic substitution reactions of 1-(phenoxycarbonyl)pyridinium ions, prepared with the essentially non-nucleophilic/non-basic fluoroborate as the counterion, have been studied using up to 1.60 M methanol in acetonitrile as solvent and under solvolytic conditions in 2,2,2-trifluoroethan-1-ol (TFE) and its mixtures with water. Under the non- solvolytic conditions, the parent and three pyridine-ring-substituted derivatives were studied. Both second-order (first-order in methanol) and third-order (second-order in methanol) kinetic contributions were observed. In the solvolysis studies, since solvent ionizing power values were almost constant over the range of aqueous TFE studied, a Grunwald–Winstein equation treatment of the specific rates of solvolysis for the parent and the 4-methoxy derivative could be carried out in terms of variations in solvent nucleophilicity, and an appreciable sensitivity to changes in solvent nucleophilicity was found.

Sign in / Sign up

Export Citation Format

Share Document