A5029235749- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Mass Spectrometry Techniques and Applications
- Spectroscopy and Quantum Chemical Studies
- Protein Structure and Dynamics
- Nanopore and Nanochannel Transport Studies
- Electrochemical Analysis and Applications
- Mitochondrial Function and Pathology
- Molecular Sensors and Ion Detection
- Ion Transport and Channel Regulation
- Fuel Cells and Related Materials
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Drug Transport and Resistance Mechanisms
- Amino Acid Enzymes and Metabolism
- Enzyme Structure and Function
- Advanced NMR Techniques and Applications
- Metabolomics and Mass Spectrometry Studies
- Analytical Chemistry and Sensors
- Photoreceptor and optogenetics research
- stochastic dynamics and bifurcation
- Nicotinic Acetylcholine Receptors Study
University of Calgary
2015-2025
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2013-2023
North-Western State Medical University named after I.I. Mechnikov
2022
North-West Public Health Research Center
2022
Institute of Solution Chemistry
1999-2019
Libin Cardiovascular Institute of Alberta
2015-2019
Universitätsklinikum Würzburg
2019
University of Alberta
2017
Calgary Laboratory Services
2015
National Institutes of Health
2014
The abnormal physicochemical characteristics of ethanol solvation in water are commonly attributed to the phenomenon hydrophobic hydration. To investigate structural organization hydration water−ethanol mixtures, we use molecular dynamics simulations based on detailed atomic models. Induced polarization is incorporated into potential function basis classical Drude oscillator model. Water−ethanol mixtures simulated at 11 molar fractions, from 0.05 0.9. Although and models parametrized...
Small metal ions play critical roles in numerous biological processes. Of particular interest is how metalloenzymes are allosterically regulated by the binding of specific ions. Understanding ion affects these processes requires atomic models that accurately treat microscopic interactions with protein ligands. Theoretical approaches at different levels sophistication can contribute to a deeper understanding systems, although computational must strike balance between accuracy and efficiency...
Rationale: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that an accepted surrogate marker for arrhythmia. But too sensitive a and not selective, resulting in many useful drugs eliminated drug discovery. Objective: To predict impact from chemistry on cardiac rhythm. Methods Results: In new linkage, we connected atomistic scale information to protein, cell, tissue scales by predicting drug-binding affinities rates simulation ion channel structure...
Electron pairs in the valence shell of an atom that do not participate bonding a molecule ("lone pairs") give rise to concentrated electron density away from center. To account for asymmetry charge arises lone pairs, electrostatic model is developed parametrically anisotropic at atomic level. The uses virtual interaction sites with partial charges are associated but coincident nuclei. In addition, incorporates polarizabilities. protocol previously outlined Anisimov et al. [J. Chem. Theory...
Inwardly rectifying potassium (Kir) channels play an important role in setting the resting membrane potential and modulating excitability. We have recently shown that cholesterol regulates representative members of Kir family majority cases, suppresses channel function. Furthermore, recent data indicate by specific sterol-protein interactions, yet location binding site is unknown. Using a combined computational-experimental approach, we show may bind to two nonanular hydrophobic regions...
Long QT syndrome, LQTS, results in serious cardiovascular disorders, such as tachyarrhythmia and sudden cardiac death. A promiscuous binding of different drugs to the intracavitary site pore domain (PD) human ether-a-go-go related gene (hERG) channels leads a similar dysfunction, known drug-induced LQTS. Therefore, an assessment blocking ability for potent is great pragmatic value molecular pharmacology medicinal chemistry hERGs. Thus, we attempted create silico model aimed at blinded drug...
Significance Voltage-gated proton (Hv1) channels play important roles in various physiological processes, such as the innate immune response. However, mechanism by which this channel closes and opens its permeation pathways is unknown, due to lack of structural information about closed open states channel. This study uses both simulation experimental approaches develop models Hv1 These suggest a for how opens. The also explaining why blocker only binds state will be essential future...
Abstract SLC4 transporters play significant roles in pH regulation and cellular sodium transport. The previously solved structures of the outward facing (OF) conformation for AE1 (SLC4A1) NBCe1 (SLC4A4) revealed an identical overall fold despite their different transport modes (chloride/bicarbonate exchange versus sodium-carbonate cotransport). However, exact mechanism determining family remains unknown. In this work, we report cryo-EM 3.4 Å structure OF NDCBE (SLC4A8), which shares...
A theoretical framework is presented to clarify the molecular determinants of ion selectivity in protein binding sites. The relative free energy a bound expressed terms main coordinating ligands coupled an effective potential mean force representing influence rest protein. latter separated into two contributions. first includes all forces keeping and confined microscopic subvolume but does not prevent from adapting smaller or larger ion. second regroups remaining that control precise...
Slo2 Na(+)-activated potassium channels are widely expressed in neurons and other cells, such as kidney, heart, skeletal muscle. Although their important physiological roles continue to be appreciated, molecular determinants responsible for sensing intracellular Na(+) remain unknown. Here we report identification of an regulatory site, similar coordination motif described Kir channels, localized the RCK2 domain Slo2.2 channels. Molecular simulations homology-modeled provided structural...
Excitatory amino acid transporters (EAATs) remove glutamate from synapses. They maintain an efficient synaptic transmission and prevent reaching neurotoxic levels. Glutamate couple the uptake of one to cotransport three sodium ions proton countertransport potassium ion. The molecular mechanism for this coupled its co- counter-transported is not known. In a crystal structure bacterial transporter homolog, Glt Ph , only two cations are bound transporter, there no indication location third...
The human ether-a-go-go related gene 1 (hERG1) K ion channel is a key element for the rapid component of delayed rectified potassium current in cardiac myocytes. Since there are no crystal structures hERG channels, creation and validation its reliable atomistic models have been targets molecular cardiology past decade. In this study, we developed vigorously validated open, closed, open-inactivated states hERG1 using multistep protocol. conserved elements were derived multiple-template...
Methods directly evaluating the hydration structure and thermodynamics of physiologically relevant cations (Na(+), K(+), Cl(-), etc.) have wide ranging applications in fields inorganic, physical, biological chemistry. All-atom simulations based on accurate potential energy surfaces appear to offer a viable option for assessing chemistry ion solvation. Although MD free solvation with classical force proven their usefulness, number challenges still remain. One them is difficulty field...
Striking structural differences between voltage-gated sodium (Nav) channels from prokaryotes (homotetramers) and eukaryotes (asymmetric, four-domain proteins) suggest the likelihood of different molecular mechanisms for common functions. For these two channel families, our data show similar selectivity sequences among alkali cations (relative permeability, Pion/PNa) asymmetric, bi-ionic reversal potentials when Na/K gradient is reversed. We performed coordinated experimental computational...