Profile
Molecular Modelling, Membrane Proteins (Ion Channels and Ion-coupled
transporters), Quantum Chemistry of Biologically Relevant Molecules, Free
Energy Profiles, Protein Structure/Function prediction
Outputs
| Title | Category | Date | Authors |
| ATP transport through VDAC and the VDAC-tubulin complex probed by equilibrium and nonequilibrium MD simulations. The University of Calgary, University of Calgary | Publication | 2013-12-01 | S. Noskov, T. K. Rostovtseva, S. M. Bezrukov | | Interactions between H562 an S5 residue in the hERG potassium channel with amino-acids in the pore helix are essential for normal functionshERG1 is a member of the cyclic nucleotide binding domain family of K+ channels. Alignment of cyclic nucleotide binding domain channels revealed an evolutionary conserved sequence HwX(A/G)C in the S5 domain. We reasoned that histidine 562 in hERG1 could play an important structure-function role. To explore this role, we created in silica models of the hERG1 pore domain based on the KvAP crystal structure with Rosetta-membrane modeling and molecular-dynamics simulations. Simulations indicate that the H562 residue in the S5 helix spans the gap between the S5 helix and the pore helix, stabilizing the pore domain, and that mutation at the H562 residue leads to a disruption of the hydrogen bonding to T618 and S621, resulting in distortion of the selectivity filter. Analysis of the simulated point mutations at positions 562/618/621 showed that the reciprocal double mutations H562W/T618I would partially restore the orientation of the 562 residue. Matching hydrophobic interactions between mutated W562 residue and I618 partially compensate for the disrupted hydrogen bonding. Complementary in vitro electrophysiological studies confirmed the results of the molecular-dynamics simulations on single mutations at positions 562, 618, and 621. Experimentally, mutations of the H562 to tryptophan produced a functional channel, but with slowed deactivation and shifted V1/2 of activation. Furthermore, the double mutation T618I/H562W rescued the defects seen in activation, deactivation, and potassium selectivity seen with the H562W mutation. In conclusion, interactions between H562 in the S5 helix and amino acids in the pore helix are important determinants of hERG1 potassium channel function, as confirmed by theory and experiment. The University of Calgary | Publication | 2009-05-01 | S. Noskov, J. P. Lees-Miller, J. O. Subbotina, J. Guo, V. Yarov-Yarovoy, H. J. Duff | | Molecular mechanism of substrate specificity in secondary amino-acid transporter LeuTThe recently published X-ray structure of LeuT, a Na(+)/Cl(-)-dependent neurotransmitter transporter, has provided fresh impetus to efforts directed at understanding the molecular principles governing specific neurotransmitter transport. The combination of the LeuT crystal structure with the results of molecular simulations enables the functional data on specific binding and transport to be related to molecular structure. All-atom FEP and molecular dynamics (MD) simulations of LeuT embedded in an explicit membrane were performed alongside a decomposition analysis to dissect the molecular determinants of the substrate specificity of LeuT. It was found that the ligand must be in a zwitterionic (ZW) form to bind tightly to the transporter. The theoretical results on the absolute binding-free energies for leucine, alanine, and glycine show that alanine can be a potent substrate for LeuT, although leucine is preferred, which is consistent with the recent experimental data (Singh et al., Nature 2007;448:952-956). Furthermore, LeuT displays robust specificity for leucine over glycine. Interestingly, the ability of LeuT to discriminate between substrates relies on the dynamics of residues that form its binding pocket (e.g., F253 and Q250) and the charged side chains (R30-D404) from a second coordination shell. The water-mediated R30-D404 salt bridge is thought to be part of the extracellular (EC) gate of LeuT. The introduction of a polar ligand such as glycine to the water-depleted binding pocket of LeuT gives rise to structural rearrangements of the R30-D404-Q250 hydrogen-bonding network and leads to increased hydration of the binding pocket. Conformational changes associated with the broken hydrogen bond between Q250 and R30 are shown to be important for tight and selective ligand binding to LeuT. The University of Calgary | Publication | 2008-12-01 | S. Noskov | | Control of Na+ selectivity in LeuT—two binding sites and two different mechanismThe x-ray structure of LeuT, a bacterial homologue of Na(+)/Cl(-)-dependent neurotransmitter transporters, provides a great opportunity to better understand the molecular basis of monovalent cation selectivity in ion-coupled transporters. LeuT possesses two ion binding sites, NA1 and NA2, which are highly selective for Na(+). Extensive all-atom free-energy molecular dynamics simulations of LeuT embedded in an explicit membrane are performed at different temperatures and various occupancy states of the binding sites to dissect the molecular mechanism of ion selectivity. The results show that the two binding sites display robust selectivity for Na(+) over K(+) or Li(+), the competing ions of most similar radii. Of particular interest, the mechanism primarily responsible for selectivity for each of the two binding sites appears to be different. In NA1, selectivity for Na(+) over K(+) arises predominantly from the strong electrostatic field arising from the negatively charged carboxylate group of the leucine substrate coordinating the ion directly. In NA2, which comprises only neutral ligands, selectivity for Na(+) is enforced by the local structural restraints arising from the hydrogen-bonding network and the covalent connectivity of the polypeptide chain surrounding the ion according to a "snug-fit" mechanism. The University of Calgary | Publication | 2008-03-01 | S. Noskov, B. Roux | | Transporters in Channel The University of Calgary | Publication | 2008-01-01 | S. Noskov | | Importance of hydration and Dynamics on the selectivity of the KcsA and NaK ChannelsFundamental concepts governing ion selectivity in narrow pores are reviewed and the microscopic factors responsible for the lack of selectivity of the NaK channel, which is structurally similar to the K+-selective KcsA channel, are elucidated on the basis of all-atom molecular dynamics free energy simulations. The results on NaK are contrasted and compared with previous studies of the KcsA channel. Analysis indicates that differences in hydration of the cation in the pore of NaK is at the origin of the lack of selectivity of NaK. The University of Calgary | Publication | 2007-02-01 | S. Noskov, B. Roux | | Ion selectivity in potassium channels.Potassium channels are tetrameric membrane-spanning proteins that provide a selective pore for the conduction of K+ across the cell membranes. One of the main physiological functions of potassium channels is efficient and very selective transport of K+ ions through the membrane to the cell. Classical views of ion selectivity are summarized within a historical perspective, and contrasted with the molecular dynamics (MD) simulations free energy perturbation (FEP) performed on the basis of the crystallographic structure of the KcsA phospholipid membrane. The results show that the KcsA channel does not select for K+ ions by providing a binding site of an appropriate (fixed) cavity size. Rather, selectivity for K+ arises directly from the intrinsic local physical properties of the ligands coordinating the cation in the binding site, and is a robust feature of a pore symmetrically lined by backbone carbonyl groups. Further analysis reveals that it is the interplay between the attractive ion–ligand (favoring smaller cation) and repulsive ligand–ligand interactions (favoring larger cations) that is the basic element governing Na+/K+ selectivity in flexible protein binding sites. Because the number and the type of ligands coordinating an ion directly modulate such local interactions, this provides a potent molecular mechanism to achieve and maintain a high selectivity in protein binding sites despite a significant conformational flexibility.
The University of Calgary | Publication | 2006-12-01 | S. Noskov, B. Roux | | Microscopic picture of hydrophobic hydration in water-ethanol mixtures from simulation with new polarizable force-fieldThe abnormal physicochemical characteristics of ethanol solvation in water are commonly attributed to the phenomenon of hydrophobic hydration. To investigate the structural organization of hydrophobic hydration in water−ethanol mixtures, we use molecular dynamics simulations based on detailed atomic models. Induced polarization is incorporated into the potential function on the basis of the classical Drude oscillator model. Water−ethanol mixtures are simulated at 11 ethanol molar fractions, from 0.05 to 0.9. Although the water and ethanol models are parametrized separately to reproduce the vaporization enthalpy, static dielectric constant, and self-diffusion constant of neat liquids at ambient conditions, they also reproduce the energetic and dynamical properties of the mixtures accurately. Furthermore, the calculated dielectric constant for the various water−alcohol mixtures is in excellent agreement with experimental data. The simulations provide a detailed structural characterization of the mixtures. A depletion of water−water hydrogen bonding in the first hydration shell of ethanol is compensated by an enhancement in the second hydration shell. The structuring effect from the second solvation shell gives rise to a net positive hydrogen-bonding excess for ethanol molar fractions up to ≃0.5. For larger molar fractions, the second hydration shell is not sufficiently populated to overcome the net H-bond depletion from the first shell. University of Calgary | Publication | 2005-04-01 | S. Noskov, B. Roux, G. Lamoureux | | Ion Permeation through the alpha-hemolysin Channel: Theoretical Studies Based on Brownian Dynamics and Poisson-Nernst-Plank Electrodiffusion TheoryIdentification of the molecular interaction governing ion conduction through biological pores is one of the most important goals of modern electrophysiology. Grand canonical Monte Carlo Brownian dynamics (GCMC/BD) and three-dimensional Poisson-Nernst-Plank (3d-PNP) electrodiffusion algorithms offer powerful and general approaches to study of ion permeation through wide molecular pores. A detailed analysis of ion flows through the staphylococcal alpha-hemolysin channel based on series of simulations at different concentrations and transmembrane potentials is presented. The position-dependent diffusion coefficient is approximated on the basis of a hydrodynamic model. The channel conductance calculated by GCMC/BD is approximately 10% higher than (electrophysiologically measured) experimental values, whereas results from 3d-PNP are always 30-50% larger. Both methods are able to capture all important electrostatic interactions in equilibrium conditions. The asymmetric conductance upon the polarity of the transmembrane potential observed experimentally is reproduced by GCMC/BD and 3d-PNP. The separation of geometrical and energetic influence of the channel on ion conduction reveals that such asymmetries arise from the permanent charge distribution inside the pore. The major determinant of the asymmetry is unbalanced charge in the triad of polar residues D127, D128, and K131. The GCMC/BD or 3d-PNP calculations reproduce also experimental reversal potentials and permeability rations in asymmetric ionic solutions. The weak anionic selectivity of the channel results from the presence of the salt bridge between E111 and K147 in the constriction zone. The calculations also reproduce the experimentally derived dependence of the reversible potential to the direction of the salt gradient. The origin of such effect arises from the asymmetrical distribution of energetic barriers along the channel axis, which modulates the preferential ion passage in different directions.
University of Calgary | Publication | 2004-10-01 | S. Noskov, B. Roux, W. Im | | Control of ion selectivity in potassium channels by electrostatic and dynamic properties of coordinating ligandsPotassium channels are essential for maintaining a normal ionic balance across cell membranes. Central to this function is the ability of such channels to support transmembrane ion conduction at nearly diffusion-limited rates while discriminating for K+ over Na+ by more than a thousand-fold. This selectivity arises because the transfer of the K+ ion into the channel pore is energetically favoured, a feature commonly attributed to a structurally precise fit between the K+ ion and carbonyl groups lining the rigid and narrow pore1. But proteins are relatively flexible structures2, 3 that undergo rapid thermal atomic fluctuations larger than the small difference in ionic radius between K+ and Na+. Here we present molecular dynamics simulations for the potassium channel KcsA, which show that the carbonyl groups coordinating the ion in the narrow pore are indeed very dynamic ('liquid-like') and that their intrinsic electrostatic properties control ion selectivity. This finding highlights the importance of the classical concept of field strength4. Selectivity for K+ is seen to emerge as a robust feature of a flexible fluctuating pore lined by carbonyl groups.
University of Calgary | Publication | 2004-10-01 | S. Noskov, S. Bernèche, B. Roux | | Long-range effects of mutating R248 to Q/W in the p53 core domainThe mutations of R248 to Trp and Gln in the core domain (CD) of the p53 protein are some of the most common mutations found in human cancer. Although the mutant 248Q and 248W p53-CDs retain the wild-type conformation and stability, they lack sequence-specific DNA binding and transactivation functions and the ability to suppress cell growth. The structural and energetic bases for the observed loss of DNA binding are unclear as the DNA-free and DNA-bound mutants are not available. Hence, we have generated three-dimensional models of the wild type, 248Q, and 248W p53-CDs, free and bound to DNA, using molecular dynamics simulations in the presence of explicit water molecules. Based on the simulation structures, the free energies of wild type and mutant p53-CDs binding to DNA have been computed and decomposed into component energies (electrostatic vs van der Waals vs cavity) and contributions from the interface residues. The DNA-free mutant structures were found to be consistent with antibody-binding and NMR data. The predicted DNA binding losses of both mutants were also in accord with experimental data. The calculations revealed that mutating R248 in the minor groove yielded long-range changes in the major groove DNA-binding interface, and the extent of these changes differs depending on the mutation type. The DNA-binding loss of the 248Q p53-CD mutant is due mainly to the loss of major groove contacts from K120 (located ∼20 Å from the mutation site) as well as unfavorable interactions of D281. In contrast, the DNA-binding loss of the 248W p53-CD mutant is due mainly to the loss of minor groove contacts from the mutant residue itself. It is also due, to a lesser extent, to the loss of major groove contacts from loop L1 and to the poorer packing of the protein−DNA interface in the 248 W mutant complex relative to the wild-type. The results obtained here are important in deciding the rescue strategy of mutant p53 DNA binding.
Royal Institute of Technology | Publication | 2002-08-01 | S. Noskov, J. D. Wright, C. Lim | | Factors governing loss and rescue of DNA binding upon single- and double- mutations in the p53 core domainThe mutation of R273-->H in the p53 core domain (p53-CD) is one of the most common mutations found in human cancers. Although the 273H p53-CD retains the wild-type conformation and stability, it lacks sequence-specific DNA binding, a transactivation function and growth suppression. However, mutating T284-->R in the 273H p53-CD restores the DNA binding affinity, and transactivation and tumour suppressor functions. Since X-ray/NMR structures of DNA-free or DNA-bound mutant p53-CD molecules are unavailable, the factors governing the loss and rescue of sequence-specific DNA binding in the 273H and 273H+284R p53-CD, respectively, are unclear. Hence, we have carried out molecular dynamics (MD) simulations of the wild-type, single mutant and double mutant p53-CD, free and DNA bound, in the presence of explicit water molecules. Based on the MD structures, the DNA-binding free energy of each p53 molecule has been computed and decomposed into component energies and contributions from the interface residues. The wild-type and mutant p53-CD MD structures were found to be consistent with the antibody-binding, X-ray and NMR data. The predicted DNA binding affinity and specificity of both mutant p53-CDs were also in accord with experimental data. The non-detectable DNA binding of the 273H p53-CD is due mainly to the disruption of a hydrogen-bonding network involving R273, D281 and R280, leading to a loss of major groove binding by R280 and K120. The restoration of DNA binding affinity and specificity of the 273H+284R p53-CD is due mainly to the introduction of another DNA-binding site at position 284, leading to a recovery of major groove binding by R280 and K120. The important role of water molecules and the DNA major groove conformation as well as implications for structure-based linker rescue of the 273H p53-CD DNA-binding affinity are discussed.
Royal Institute of Technology | Publication | 2002-04-01 | S. Noskov, J. D. Wright, C. Lim | | Free energy decomposition of protein-protein interactionsA free energy decomposition scheme has been developed and tested on antibody-antigen and protease-inhibitor binding for which accurate experimental structures were available for both free and bound proteins. Using the x-ray coordinates of the free and bound proteins, the absolute binding free energy was computed assuming additivity of three well-defined, physical processes: desolvation of the x-ray structures, isomerization of the x-ray conformation to a nearby local minimum in the gas-phase, and subsequent noncovalent complex formation in the gas phase. This free energy scheme, together with the Generalized Born model for computing the electrostatic solvation free energy, yielded binding free energies in remarkable agreement with experimental data. Two assumptions commonly used in theoretical treatments; viz., the rigid-binding approximation (which assumes no conformational change upon complexation) and the neglect of vdW interactions, were found to yield large errors in the binding free energy. Protein-protein vdW and electrostatic interactions between complementary surfaces over a relatively large area (1400--1700 A(2)) were found to drive antibody-antigen and protease-inhibitor binding.
University of Calgary | Publication | 2001-08-01 | S. Noskov, C. Lim | | Structure of methanol-methanol associates in dilute methanol-water mixtures from molecular dynamics simulationsMolecular dynamics simulations have been performed for 8 methanol-water solutions using rigid and flexible potential models. The heat capacity, the radial distribution functions and potential mean force obtained by MD simulations were compared to previous simulations and experimental results. Special attention has been paid to the anomalous behaviour of the heat capacity of dilute aqueous solutions of methanol. This behaviour can be attributed to a cooperative effect resulting from methanol-methanol associations.
University of Calgary | Publication | 2001-05-01 | S. Noskov, A. M. Kolker, B. M. Rode, M. Kiselev | | A study of anomalous heat capacity dependence in the methanol-water mixtures from Molecular Dynamics simulationsThe molecular dynamic (MD) method is used to study the anomalous behavior of heat capacity in the range of small concentrations of methanol-water solutions. The behavior of the concentration dependence of heat capacity as calculated by the MD method qualitatively coincides with the experimental values. The calculation of contributions from different types of interaction to heat capacity showed that the greatest contribution is made by the interaction between the methanol molecules. The reason for the anomalous behavior of heat capacity is discussed based on the calculation of the mean force potential, radial distribution functions, and hydrogen bond network parameters.
Russian Academy of Sciences | Publication | 1999-03-01 | S. Noskov, M. Kiselev, A. M. Kolker | | QM/MM calculations with deMon2k University of Calgary, The University of Calgary | Publication | 2015-01-01 | D. Salahub, S. Noskov, B. Lev, R. Zhang, V. Ngo, A. Goursot, P. Calaminici, A. M. Köster, A. Alvarez-Ibarra, D. Mejía-Rodríguez, J. Řezáč, F. Cailliez, A. d. Lande | | Elucidating Factors Important for Monovalent Cation Selectivity in Enzymes: E. coli β-Galactosidase as a Model The University of Calgary, University of Calgary | Publication | 2015-01-01 | R. W. Juers, S. Noskov | | The molecular mechanism of ion-dependent gating in secondary transporters. The University of Calgary, University of Calgary | Publication | 2013-10-01 | C. Zhao, S. Noskov | | Identification of novel cholesterol-binding regions in Kir2 channels. The University of Calgary, University of Calgary | Publication | 2013-10-01 | A. Rosenhouse-Dantsker, S. Noskov, S. Durdagi, D. E. Logothetis, I. Levitan | | Cholesterol sensitivity of KIR2.1 depends on Functional inter-links between the N and C termini. National Institutes of Health, The University of Calgary, University of Calgary | Publication | 2013-06-01 | A. Rosenhouse-Dantsker, S. Noskov, D. E. Logothetis, I. Levitan | | Role of protein matrix rigidity and local polarization effects in the monovalent cation selectivity of crystallographic sites in the Na-coupled aspartate transporter Glt(Ph). National Institutes of Health, The University of Calgary, University of Calgary | Publication | 2013-02-01 | B. Lev, S. Noskov | | Distant cytosolic residues mediate a two-way molecular switch that controls the modulation of inwardly rectifying potassium (Kir) channels by cholesterol and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)). National Institutes of Health, The University of Calgary | Publication | 2012-11-01 | A. Rosenhouse-Dantsker, S. Noskov, H. Han, S. K. Adney, Q. Y. Tang, A. A. Rodríguez-Menchaca, G. B. Kowalsky, V. I. Petrou, C. V. Osborn, D. E. Logothetis, I. Levitan | | Mechanism of K+/Na+ selectivity in potassium channels from the perspective of the non-selective bacterial channel NaK. The University of Calgary | Publication | 2011-05-01 | S. Durdagi, S. Noskov | | Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations. The University of Calgary | Publication | 2010-11-01 | J. Subbotina, S. Noskov | | Hydration number, topological control, and ion selectivity. The University of Calgary | Publication | 2009-06-01 | H. Yu, S. Noskov, B. Roux | | Pendular Proteins in Gases and New Avenues for Characterization of Macromolecules by Ion Mobility SpectrometryPolar molecules align in electric fields when the dipole energy (proportional to field intensity E x dipole moment p) exceeds the thermal rotational energy. Small molecules have low p and align only at inordinately high E or upon extreme cooling. Many biomacromolecules and ions are strong permanent dipoles that align at E achievable in gases and room temperature. The collision cross-sections of aligned ions with gas molecules generally differ from orientationally averaged quantities, affecting ion mobilities measured in ion mobility spectrometry (IMS). Field asymmetric waveform IMS (FAIMS) separates ions by the difference between mobilities at high and low E and hence can resolve and identify macroion conformers based on the mobility difference between pendular and free rotor states. The exceptional sensitivity of that difference to ion geometry and charge distribution holds the potential for a powerful method for separation and characterization of macromolecular species. Theory predicts that the pendular alignment of ions in gases at any E requires a minimum p that depends on the ion mobility, gas pressure, and temperature. At ambient conditions used in current FAIMS systems, p for realistic ions must exceed approximately 300-400 Debye. The dipole moments of proteins statistically increase with increasing mass, and such values are typical above approximately 30 kDa. As expected for the dipole-aligned regime, FAIMS analyses of protein ions and complexes of approximately 30-130 kDa show an order-of-magnitude expansion of separation space compared with smaller proteins and other ions. The University of Calgary | Publication | 2009-04-01 | A. A. Shvartsburg, S. Noskov, R. W. Purves, R. D. Smith | | The study of hydrophobic hydration in supercritical water-methanol mixtures. University of Calgary | Publication | 2001-01-01 | M. Kiselev, S. Noskov, Y. Puhovski, T. Kerdcharoen, S. Hannongbua | | Molecular Strategies to Achieve Selective Conductance in NaK Channel Variants. University of Calgary, The University of Calgary | Publication | 2014-02-01 | Y. Wang, A. C. Chamberlin, S. Noskov | | Molecular Mechanism of Ion-Ion and Ion-Substrate Coupling in the Na+-dependent leucine transporter LeuTIon-coupled transport of neurotransmitter molecules by neurotransmitter:sodium symporters (NSS) play an important role in the regulation of neuronal signaling. One of the major events in the transport cycle is ion-substrate coupling and formation of the high-affinity occluded state with bound ions and substrate. Molecular mechanisms of ion-substrate coupling and the corresponding ion-substrate stoichiometry in NSS transporters has yet to be understood. The recent determination of a high-resolution structure for a bacterial homolog of Na(+)/Cl(-)-dependent neurotransmitter transporters, LeuT, offers a unique opportunity to analyze the functional roles of the multi-ion binding sites within the binding pocket. The binding pocket of LeuT contains two metal binding sites. The first ion in site NA1 is directly coupled to the bound substrate (Leu) with the second ion in the neighboring site (NA2) only approximately 7 A away. Extensive, fully atomistic, molecular dynamics, and free energy simulations of LeuT in an explicit lipid bilayer are performed to evaluate substrate-binding affinity as a function of the ion load (single versus double occupancy) and occupancy by specific monovalent cations. It was shown that double ion occupancy of the binding pocket is required to ensure substrate coupling to Na(+) and not to Li(+) or K(+) cations. Furthermore, it was found that presence of the ion in site NA2 is required for structural stability of the binding pocket as well as amplified selectivity for Na(+) in the case of double ion occupancy. The University of Calgary | Publication | 2008-11-01 | D. A. Caplan, J. O. Subbotina, S. Noskov | | Na(+), K (+) and Tl(+) hydration from QM/MM computations and MD simulations with a polarizable force field. The University of Calgary | Publication | 2010-03-01 | B. Lev, D. R. Salahub, S. Noskov | | BROMOC suite: Monte Carlo/Brownian dynamics suite for studies of ion permeation and DNA transport in biological and artificial pores with effective potentials The University of Calgary, University of Calgary | Publication | 2014-12-01 | P. M. Biase, S. Markosyan, S. Noskov | | Modeling of open, closed, and open-inactivated states of the hERG1 channel: structural mechanisms of the state-dependent drug binding. National Institutes of Health, The University of Calgary | Publication | 2012-10-01 | S. Durdagi, S. Deshpande, H. J. Duff, S. Noskov | | Atomistic models for free energy evaluation of drug binding to membrane proteins. The University of Calgary | Publication | 2011-01-01 | S. Durdagi, C. Zhao, J. E. Cuervo, S. Noskov | | The RCK2 domain uses a coordination site present in Kir channels to confer sodium sensitivity to Slo2.2 channels The University of Calgary | Publication | 2010-07-01 | Z. Zhang, A. Rosenhouse-Dantsker, Q. Y. Tang, S. Noskov, D. E. Logothetis | | A guide to QM/MM methodology and applications University of Calgary, The University of Calgary | Publication | 2010-06-01 | R. Zhang, B. Lev, J. E. Cuervo, S. Noskov, D. Salahub | | Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy. University of Calgary, The University of Calgary | Publication | 2014-02-01 | R. K. Finol-Urdaneta, Y. Wang, A. Al-Sabi, C. Zhao, S. Noskov, R. J. French | | Hydrophobic plug functions as a gate in voltage-gated proton channels. University of Calgary, The University of Calgary | Publication | 2014-01-01 | A. Chamberlin, F. Qiu, S. Rebolledo, Y. Wang, S. Noskov, H. P. Larsson | | Ion-controlled conformational dynamics in the outward-open transition from an occluded state of LeuT. National Institutes of Health, The University of Calgary | Publication | 2012-09-01 | C. Zhao, S. Stolzenberg, L. Gracia, H. Weinstein, S. Noskov, L. Shi | | BROMOC-D: Brownian Dynamics/Monte-Carlo Program Suite to Study Ion and DNA Permeation in Nanopores. The University of Calgary | Publication | 2012-07-01 | P. M. De, C. J. Solano, S. Markosyan, L. Czapla, S. Noskov | | Atomic level anisotropy in the electrostatic modeling of lone pairs for a polarizable force field based on classical drude oscillator.Electron pairs in the valence shell of an atom that do not participate in the bonding of a molecule (“lone pairs”) give rise to a concentrated electron density away from the atom center. To account for the asymmetry in the electron charge density that arises from lone pairs, an electrostatic model is developed that is parametrically anisotropic at the atomic level. The model uses virtual interaction sites with partial charges that are associated but not coincident with the nuclei. In addition, the model incorporates anisotropic atomic polarizabilities. The protocol previously outlined in Anisimov et al. [J. Chem. Theory Comput. 2005, 1, 153] for parametrizing the electrostatic potential energy of a polarizable force field using classical Drude oscillators is extended to incorporate additional lone pair parameters. To probe the electrostatic environment around the lone pairs, the static (molecule alone) and perturbed (molecule in the presence of a test charge) electrostatic potential (ESP) are evaluated and compared to high level quantum mechanical (QM) electronic structure calculations. The parametrization of the virtual sites relies on data from the QM static ESP. The contribution to the perturbed ESP from the electronic polarization of the molecule is used to resolve the components of the atomic polarizability tensor. The model is tested in the case of four molecules: methanol, acetone, methylamine, and pyridine. Interaction energies with water and sodium are used to assess the accuracy of the model. The results are compared with simpler models placing all the charge on the nuclei as well as using only isotropic atomic polarizabilities. Analysis shows that the addition of virtual sites reduces the average error relative to the QM calculations. In contrast to models with atom centered charges, the virtual site models correctly predict the minimum energy conformation for acetone and methanol, with water, to be closely coordinated with the lone pair direction. Furthermore, addition of anisotropic atomic polarizabilities to the virtual site model allows for precise fitting to the local perturbed QM ESP. The University of Calgary | Publication | 2007-10-01 | E. Harder, V. Anisimov, I. V. Vorobyov, P. E. Lopes, S. Noskov, A. D. Jr, B. Roux | | The study of supercritical water-methanol mixturesWe investigated hydrophobic hydration and heat capacity (CV) of diluted aqueous solutions of methanol at supercritical region using molecular dynamics method. We performed simulations for several concentrations of methanol and densities of mixtures. Similar to that observed for ambient conditions, the 600 K solution containing 0.12 mole fraction of methanol at the density of 0.98 gm.cm-3 yields the highest CV. The intermolecular structure between water and methanol molecules at this concentration was also found to be enhanced. Hydrophobic hydration, relative to ambient conditions, is diminished slightly at the concentration of Cv maximum and diminishes drastically for the other concentrations.
University of Calgary | Publication | 2001-06-01 | M. Kiselev, Y. Puhovski, T. Kerdcharoen, S. Hannongbua, S. Noskov | | The QM-MM interface for CHARMM-deMon. University of Calgary, The University of Calgary | Publication | 2010-04-01 | B. Lev, R. Zhang, A. l. de, D. Salahub, S. Noskov | | Representation of ion-protein interactions using the Drude polarizable force-field University of Calgary, The University of Calgary | Publication | 2015-01-01 | H. Li, V. Ngo, M. C. Silva, D. Salahub, K. Kallahan, B. Roux, S. Noskov | | An Integrated Approach to Elucidate the Mechanism of Action of the hERG (KCNH2) Activator, NS1643: Novel Binding Site at the Voltage Sensor in the Neighborhood of L529 and K525 The University of Calgary, University of Calgary | Publication | 2015-02-01 | G. Jiqing, C. Y. May, J. P. Miller, L. L. Perissinotti, T. Claydon, S. Durdagi, S. Noskov, H. J. Duff | | Evidence for a third sodium-binding site in glutamate transporters suggests an ion/substrate coupling model. The University of Calgary | Publication | 2010-06-01 | H. P. Larsson, X. Wang, B. Lev, I. Baconguis, D. A. Caplan, N. P. Vyleta, H. P. Koch, A. Diez-Sampedro, S. Noskov | | Mechanism of the Association between Na $\mathplus$ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters The University of Calgary, University of Calgary | Publication | 2015-04-01 | S. Stolzenberg, M. Quick, C. Zhao, K. Gotfryd, G. Khelashvili, U. Gether, C. J. Loland, J. A. Javitch, S. Noskov, H. Weinstein, L. Shi | | A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport The University of Calgary | Publication | 2011-09-01 | L. K. Henry, H. Iwamoto, J. R. Field, K. Kaufmann, E. S. Dawson, M. T. Jacobs, C. Adams, B. Felts, I. Zdravkovic, V. Armstrong, S. Combs, E. Solis, G. Rudnick, S. Noskov, L. J. DeFelice, J. Meiler, R. D. Blakely |
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