Electrostatic free energy calculations using the generalized solvent boundary potential method

Copyright 2002 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in The Journal of Chemical Physics and may be found at http://dx.doi.org/10.1063/1.1507108.Free energyperturbation (FEP) calculations using all-atom molecular dynamics simulations with a large number of explicit solvent molecules are a powerful approach to study ligand–macromolecule association processes at the atomic level. One strategy to carry out FEP calculations efficiently and reduce computational time is to consider the explicit dynamics of only a small number of atoms in a localized region around the ligand. Such an approximation is motivated by the observation that the factors governing binding specificity are dominated by interactions in the vicinity of the ligand. However, a straightforward truncation of the system may yield inaccurate results as the influence exerted by the remote regions of the macromolecule and the surrounding solvent through long-range electrostatic effects may be significant. To obtain meaningful results, it is important to incorporate the influence of the remote regions of the ligand–macromolecule complex implicitly using some effective potential. The generalized solvent boundary potential (GSBP) that was developed recently [W. Im, S. Bernèche, and B. Roux, J. Chem. Phys. 114, 2924 (2001)] is an efficient computational method to represent the long-range electrostaticinteractions arising from remote (outer) regions in simulations of a localized (inner) region with a small number of explicit atoms. In the present work, FEP calculations combined with GSBP are used to illustrate the importance of these long-range electrostatic factors in estimation of the charging free energy of an aspartate ligand bound to the aspartyl-tRNA synthetase. Calculations with explicit spherical simulation inner regions of different radii are used to test the accuracy of the GSBP method and also illustrate the importance of explicit protein and solvent dynamics in the free energy estimation. The influence of the represented outer region is tested using separate simulations in which the reaction field and/or the protein static field are excluded. Both components are shown to be essential to obtain quantitatively meaningful results. The ability of implicitly treating the influence of protein fluctuations in the outer region using a protein dielectric constant is examined. It is shown that accurate charging free energy calculations can be performed for this system with a spherical region of 15 to 20 Å radius, which roughly corresponds to 1500–3500 moving atoms. The results indicate that GSBP in combination with FEP calculations is a precise and efficient approach to include long-range electrostatic effects in the study of ligand binding to large macromolecules

1-Hydroxy-2(1H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson’s Disease

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson’s disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood–brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation

Coffee and tea consumption in relation to inflammation and basal glucose metabolism in a multi-ethnic Asian population: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Higher coffee consumption has been associated with a lower risk of type 2 diabetes in cohort studies, but the physiological pathways through which coffee affects glucose metabolism are not fully understood. The aim of this study was to evaluate the associations between habitual coffee and tea consumption and glucose metabolism in a multi-ethnic Asian population and possible mediation by inflammation.</p> <p>Methods</p> <p>We cross-sectionally examined the association between coffee, green tea, black tea and Oolong tea consumption and glycemic (fasting plasma glucose, HOMA-IR, HOMA-beta, plasma HbA1c) and inflammatory (plasma adiponectin and C-reactive protein) markers in a multi-ethnic Asian population (N = 4139).</p> <p>Results</p> <p>After adjusting for multiple confounders, we observed inverse associations between coffee and HOMA-IR (percent difference: - 8.8% for ≥ 3 cups/day versus rarely or never; <it>P_trend</it>= 0.007), but no significant associations between coffee and inflammatory markers. Tea consumption was not associated with glycemic markers, but green tea was inversely associated with plasma C-reactive protein concentrations (percent difference: - 12.2% for ≥ 1 cup/day versus < 1 cup/week; <it>P_trend</it>= 0.042).</p> <p>Conclusions</p> <p>These data provide additional evidence for a beneficial effect of habitual caffeinated coffee consumption on insulin sensitivity, and suggest that this effect is unlikely to be mediated by anti-inflammatory mechanisms.</p

Legalised non-consensual sterilisation - eugenics put into practice before 1945, and the aftermath. Part 1: USA, Japan, Canada and Mexico.

In the late 19th century, eugenics, a pseudo-scientific doctrine based on an erroneous interpretation of the laws of heredity, swept across the industrialised world. Academics and other influential figures who promoted it convinced political stakeholders to enact laws authorising the sterilisation of people seen as ‘social misfits’. The earliest sterilisation Act was enforced in Indiana, in 1907; most States in the USA followed suit and so did several countries, with dissimilar political regimes. The end of the Second World War saw the suspension of Nazi legislation in Germany, including that regulating coerced sterilisation. The year 1945 should have been the endpoint of these inhuman practices but, in the early post-war period, the existing sterilisation Acts were suspended solely in Germany and Austria. Only much later did certain countries concerned – not Japan so far - officially acknowledge the human rights violations committed, issue apologies, and develop reparation schemes for the victims’ benefit

Effects of Short-Term Continuous Montmorency Tart Cherry Juice Supplementation in Participants with Metabolic Syndrome

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s00394-020-02355-5Purpose: Metabolic Syndrome (MetS) augments the incidence of cardiovascular disease by two-fold and type II diabetes mellitus by five-fold. Montmorency tart cherries are rich in phytochemicals shown to improve biomarkers related to cardio-metabolic health in humans. This study aimed to examine cardio-metabolic responses after 7-days Montmorency tart cherry juice (MTCJ) supplementation and also acute on short-term supplementation responses to a single bolus, in humans with MetS. Methods: In a randomised, single-blind, placebo-controlled, crossover trial, 12 participants with MetS (50 ± 10 years; 6M/6F), consumed MTCJ or placebo (PLA) for 7 days. Blood-based and functional cardio-metabolic biomarkers were measured pre- and post-supplementation, and acute responses measured pre-bolus and up to 5 h post-bolus on the 7th day. Results: 24-h ambulatory systolic (P = 0.016), diastolic (P = 0.009) blood pressure and mean arterial pressure (P = 0.041) were significantly lower after 7-days MTCJ supplementation compared to PLA. Glucose (P = 0.038), total cholesterol (P = 0.036), LDL (P = 0.023) concentrations, total cholesterol:HDL ratio (P = 0.004) and respiratory exchange ratio values (P = 0.009) were significantly lower after 6-days MTCJ consumption compared to PLA. Conclusions: This study revealed for the first time in humans that MTCJ significantly improved 24-h BP, fasting glucose, total cholesterol and total cholesterol:HDL ratio, and also lowered resting respiratory exchange ratio compared to a control group. Responses demonstrated clinically relevant improvements on aspects of cardio-metabolic function, emphasising the potential efficacy of MTCJ in preventing further cardio-metabolic dysregulation in participants with MetS. Registered at clinicaltrials.gov (NCT03619941).Peer reviewedFinal Accepted Versio

Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins

E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins

Bath Breakfast Project (BBP) - Examining the role of extended daily fasting in human energy balance and associated health outcomes: Study protocol for a randomised controlled trial [ISRCTN31521726]

<p>Abstract</p> <p>Background</p> <p>Current guidance regarding the role of daily breakfast in human health is largely grounded in cross-sectional observations. However, the causal nature of these relationships has not been fully explored and what limited information is emerging from controlled laboratory-based experiments appears inconsistent with much existing data. Further progress in our understanding therefore requires a direct examination of how daily breakfast impacts human health under free-living conditions.</p> <p>Methods/Design</p> <p>The Bath Breakfast Project (BBP) is a randomised controlled trial comparing the effects of daily breakfast consumption relative to extended fasting on energy balance and human health. Approximately 70 men and women will undergo extensive laboratory-based assessments of their acute metabolic responses under fasted and post-prandial conditions, to include: resting metabolic rate, substrate oxidation, dietary-induced thermogenesis and systemic concentrations of key metabolites/hormones. Physiological and psychological indices of appetite will also be monitored both over the first few hours of the day (i.e. whether fed or fasted) and also following a standardised test lunch used to assess voluntary energy intake under controlled conditions. Baseline measurements of participants' anthropometric characteristics (e.g. DEXA) will be recorded prior to intervention, along with an oral glucose tolerance test and acquisition of adipose tissue samples to determine expression of key genes and estimates of tissue-specific insulin action. Participants will then be randomly assigned either to a group prescribed an energy intake of ≥3000 kJ before 1100 each day or a group to extend their overnight fast by abstaining from ingestion of energy-providing nutrients until 1200 each day, with all laboratory-based measurements followed-up 6 weeks later. Free-living assessments of energy intake (via direct weighed food diaries) and energy expenditure (via combined heart-rate/accelerometry) will be made during the first and last week of intervention, with continuous glucose monitors worn both to document chronic glycaemic responses to the intervention and to verify compliance.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN31521726">ISRCTN31521726</a>.</p

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases.

We have calculated the reorganization energy for the intramolecular electron transfer between the reduced type 1 copper site and the peroxy intermediate of the trinuclear cluster in the multicopper oxidase CueO. The calculations are performed at the combined quantum mechanics and molecular mechanics (QM/MM) level, based on molecular dynamics simulations with tailored potentials for the two copper sites. We obtain a reorganization energy of 91-133 kJ/mol, depending on the theoretical treatment. The two Cu sites contribute by 12 and 22 kJ/mol to this energy, whereas the solvent contribution is 34 kJ/mol. The rest comes from the protein, involving small contributions from many residues. We have also estimated the energy difference between the two electron-transfer states and show that the reduction of the peroxy intermediate is exergonic by 43-87 kJ/mol, depending on the theoretical method. Both the solvent and the protein contribute to this energy difference, especially charged residues close to the two Cu sites. We compare these estimates with energies obtained from QM/MM optimizations and QM calculations in a vacuum and discuss differences between the results obtained at various levels of theory

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism

Without Apology: Writings on Abortion in Canada

Until the late 1960s, the authorities on abortion were for the most part men—politicians, clergy, lawyers, physicians, all of whom had an interest in regulating women’s bodies. Even today, when we hear women speak publicly about abortion, the voices are usually those of the leaders of women’s and abortion rights organizations, women who hold political office, and, on occasion, female physicians. We also hear quite frequently from spokeswomen for anti-abortion groups. Rarely, however, do we hear the voices of ordinary women—women whose lives have been in some way touched by abortion. Their thoughts typically owe more to human circumstance than to ideology, and without them, we run the risk of thinking and talking about the issue of abortion only in the abstract. Without Apology seeks to address this issue by gathering the voices of activists, feminists, and scholars as well as abortion providers and clinic support staff alongside the stories of women whose experience with abortion is more personal. With the particular aim of moving beyond the polarizing rhetoric that has characterized the issue of abortion and reproductive justice for so long, Without Apology is an engrossing and arresting account that will promote both reflection and discussion.Canada Council for the Arts Government of Canada Canada Book Fund (CFB) Government of Alberta, Alberta Media Fun