| 1. |
- Aponte-Santamaria, Camilo, et al.
(författare)
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Dynamics and energetics of solute permeation through the Plasmodium falciparum aquaglyceroporin
- 2010
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 12:35, s. 10246-10254
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Tidskriftsartikel (refereegranskat)abstract
- The aquaglyceroporin from Plasmodium falciparum (PfAQP) is a potential drug target for the treatment of malaria. It efficiently conducts water and other small solutes, and is proposed to intervene in several crucial physiological processes during the parasitic life cycle. Despite the wealth of experimental data available, a dynamical and energetic description at the single-molecule level of the solute permeation through PfAQP has been lacking so far. Here we address this question by using equilibrium and umbrella sampling molecular dynamics simulations. We computed the water osmotic permeability coefficient, the pore geometry and the potential of mean force for the permeation of water, glycerol and urea. Our simulations show that the PfAQP, the human aquaporin 1 (hAQP1) and the Escherichia coli glycerol facilitator (GlpF) have nearly identical water permeabilities. The Arg196 residue at the ar/R region was found to play a crucial role regulating the permeation of water, glycerol and urea. The computed free energy barriers at the ar/R selectivity filter corroborate that PfAQP conducts glycerol at higher rates than urea, and suggest that PfAQP is a more efficient glycerol and urea channel than GlpF. Our results are consistent with a solute permeation mechanism for PfAQP which is similar to the one established for other members of the aquaglyceroporin family. In this mechanism, hydrophobic regions near the NPA motifs are the main water rate limiting barriers, and the replacement of water-arg196 interactions and solute-matching in the hydrophobic pocket at the ar/R region are the main determinants underlying selectivity for the permeation of solutes like glycerol and urea.
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| 2. |
- Caleman, Carl, et al.
(författare)
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Atomistic simulation of ion solvation in water explains surface preference of halides
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 6838-6842
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Tidskriftsartikel (refereegranskat)abstract
- Water is a demanding partner. It strongly attracts ions, yet some halide anions-chloride, bromide, and iodide-are expelled to the air/water interface. This has important implications for chemistry in the atmosphere, including the ozone cycle. We present a quantitative analysis of the energetics of ion solvation based on molecular simulations of all stable alkali and halide ions in water droplets. The potentials of mean force for Cl-, Br-, and I-have shallow minima near the surface. We demonstrate that these minima derive from more favorable water-water interaction energy when the ions are partially desolvated. Alkali cations are on the inside because of the favorable ion-water energy, whereas F-is driven inside by entropy. Models attempting to explain the surface preference based on one or more ion properties such as polarizability or size are shown to lead to qualitative and quantitative errors, prompting a paradigm shift in chemistry away from such simplifications.
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| 3. |
- Caleman, Carl, et al.
(författare)
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Force Field Benchmark of Organic Liquids : Density, Enthalpy of Vaporization, Heat Capacities, Surface Tension, Isothermal Compressibility, Volumetric Expansion Coefficient, and Dielectric Constant
- 2012
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 8:1, s. 61-74
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Tidskriftsartikel (refereegranskat)abstract
- The chemical composition of small organic molecules is often very similar to amino acid side chains or the bases in nucleic acids, and hence there is no a priori reason why a molecular mechanics force field could not describe both organic liquids and biomolecules with a single parameter set. Here, we devise a benchmark for force fields in order to test the ability of existing force fields to reproduce some key properties of organic liquids, namely, the density, enthalpy of vaporization, the surface tension, the heat capacity at constant volume and pressure, the isothermal compressibility, the volumetric expansion coefficient, and the static dielectric constant. Well over 1200 experimental measurements were used for comparison to the simulations of 146 organic liquids. Novel polynomial interpolations of the dielectric constant (32 molecules), heat capacity at constant pressure (three molecules), and the isothermal compressibility (53 molecules) as a function of the temperature have been made, based on experimental data, in order to be able to compare simulation results to them. To compute the heat capacities, we applied the two phase thermodynamics method (Lin et al. J. Chem. Phys. 2003, 119, 11792), which allows one to compute thermodynamic properties on the basis of the density of states as derived from the velocity autocorrelation function. The method is implemented in a new utility within the GROMACS molecular simulation package, named g_dos, and a detailed expose of the underlying equations is presented. The purpose of this work is to establish the state of the art of two popular force fields, OPLS/AA (all-atom optimized potential for liquid simulation) and GAFF (generalized Amber force field), to find common bottlenecks, i.e., particularly difficult molecules, and to serve as a reference point for future force field development. To make for a fair playing field, all molecules were evaluated with the same parameter settings, such as thermostats and barostats, treatment of electrostatic interactions, and system size (1000 molecules). The densities and enthalpy of vaporization from an independent data set based on simulations using the CHARMM General Force Field (CGenFF) presented by Vanommeslaeghe et al. (J. Comput. Chem. 2010, 31, 671) are included for comparison. We find that, overall, the OPLS/AA force field performs somewhat better than GAFF, but there are significant issues with reproduction of the surface tension and dielectric constants for both force fields.
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| 4. |
- Ekholm, Victor, et al.
(författare)
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Propensity, free energy contributions and conformation of primary : N -alcohols at a water surface
- 2021
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 23:34, s. 18823-18829
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric aerosols contain organic molecules that serve as cloud condensation nucleation sites and affect the climate. Several experimental and simulation studies have been dedicated to investigate their surface propensity, but the mechanisms that drive them to the water surface are still not fully understood. In this molecular dynamics (MD) simulation study, primary alcohols are considered as a model system representing polar organic molecules. We find that the surface affinity of n-alcohols increases linearly with the length of the hydrophobic tail. By decomposing the adsorption free energy into enthalpy and entropy contributions, we find that the transition from bulk to surface is entropically driven, compatible with the fact that the hydrophobic effect of small solutes is of entropic origin. The enthalpy of surface adsorption is nearly invariant among different n-alcohols because the loss of solvent-alcohol interactions is balanced by a gain in solvent-solvent interactions. Structural analysis shows that, at the surface, the linear alcohols prefer an orientation with the hydrophobic tail pointing out from the surface, whereas the hydroxyl group remains buried in the water. This general behaviour is likely transferable to other small molecules with similar structures but other functional groups that are present in the atmosphere. Therefore, the present study is a step forward toward a general description of organic molecules in aerosols.
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| 5. |
- Hub, Jochen S., et al.
(författare)
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g_wham-A Free Weighted Histogram Analysis Implementation Including Robust Error and Autocorrelation Estimates
- 2010
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 6:12, s. 3713-3720
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Tidskriftsartikel (refereegranskat)abstract
- The Weighted Histogram Analysis Method (WHAM) is a standard technique used to compute potentials of mean force (PMFs) from a set of umbrella sampling simulations. Here, we present a new WHAM implementation, termed g_wham, which is distributed freely with the GROMACS molecular simulation suite. g_wham estimates statistical errors using the technique of bootstrap analysis. Three bootstrap methods are supported: (i) bootstrapping new trajectories based on the umbrella histograms, (ii) bootstrapping of complete histograms, and (iii) Bayesian bootstrapping of complete histograms, that is, bootstrapping via the assignment of random weights to the histograms. Because methods ii and iii consider only complete histograms as independent data points, these methods do not require the accurate calculation of autocorrelation times. We demonstrate that, given sufficient sampling, bootstrapping new trajectories allows for an accurate error estimate. In the presence of long autocorrelations, however, (Bayesian) bootstrapping of complete histograms yields a more reliable error estimate, whereas bootstrapping of new trajectories may underestimate the error. In addition, we emphasize that the incorporation of autocorrelations into WHAM reduces the bias from limited sampling, in particular, when computing periodic PMFs in inhomogeneous systems such as solvated lipid membranes or protein channels.
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| 6. |
- Hub, Jochen S., et al.
(författare)
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Potentials of Mean Force and Permeabilities for Carbon Dioxide, Ammonia, and Water Flux across a Rhesus Protein Channel and Lipid Membranes
- 2010
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 132:38, s. 13251-13263
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Tidskriftsartikel (refereegranskat)abstract
- As a member of the ubiquitous ammonium transporter/methylamine permease/Rhesus (Amt/MEP/Rh) family of membrane protein channels, the 50 kDa Rhesus channel (Rh50) has been implicated in ammonia (NH3) and, more recently, also in carbon dioxide (CO2) transport. Here we present molecular dynamics simulations of spontaneous full permeation events of ammonia and carbon dioxide across Rh50 from Nitrosomonas europaea. The simulations show that Rh50 is functional in its crystallographic conformation, without the requirement for a major conformational change or the action of a protein partner. To assess the physiological relevance of NH3 and CO2 permeation across Rh50, we have computed potentials of mean force (PMFs) and permeabilities for NH3 and CO2 flux across Rh50 and compare them to permeation through a wide range of lipid membranes, either composed of pure lipids or composed of lipids plus an increasing cholesterol content. According to the PMFs, Rh50 is expected to enhance NH3 flux across dense membranes, such as membranes with a substantial cholesterol content. Although cholesterol reduces the intrinsic CO2 permeability of lipid membranes, the CO2 permeabilities of all membranes studied here are too high to allow significant Rh50-mediated CO2 flux. The increased barrier in the PMF for water permeation across Rh50 shows that Rh50 discriminates 40-fold between water and NH3. Thus, Rh50 channels complement aquaporins, allowing the cell to regulate water and NH3 flux independently. The PMFs for methylamine and NH3 are virtually identical, suggesting that methylamine provides an excellent model for NH3 in functional experiments.
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| 7. |
- Hub, Jochen S., et al.
(författare)
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Spontaneous Quaternary and Tertiary T-R Transitions of Human Hemoglobin in Molecular Dynamics Simulation
- 2010
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 6:5, s. e1000774-
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Tidskriftsartikel (refereegranskat)abstract
- We present molecular dynamics simulations of unliganded human hemoglobin (Hb) A under physiological conditions, starting from the R, R2, and T state. The simulations were carried out with protonated and deprotonated HC3 histidines His(beta)146, and they sum up to a total length of 5.6 mu s. We observe spontaneous and reproducible T-->R quaternary transitions of the Hb tetramer and tertiary transitions of the alpha and beta subunits, as detected from principal component projections, from an RMSD measure, and from rigid body rotation analysis. The simulations reveal a marked asymmetry between the alpha and beta subunits. Using the mutual information as correlation measure, we find that the beta subunits are substantially more strongly linked to the quaternary transition than the alpha subunits. In addition, the tertiary populations of the alpha and beta subunits differ substantially, with the beta subunits showing a tendency towards R, and the alpha subunits showing a tendency towards T. Based on the simulation results, we present a transition pathway for coupled quaternary and tertiary transitions between the R and T conformations of Hb.
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| 8. |
- Hub, Jochen S., et al.
(författare)
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Thermodynamics of hydronium and hydroxide surface solvation
- 2014
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Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6520 .- 2041-6539. ; 5:5, s. 1745-1749
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Tidskriftsartikel (refereegranskat)abstract
- The concentration of hydronium and hydroxide at the water-air interface has been debated for a long time. Recent evidence from a range of experiments and theoretical calculations strongly suggests the water surface to be somewhat acidic. Using novel polarizable models we have performed potential of mean force calculations of a hydronium ion, a hydroxide ion and a water molecule in a water droplet and a water slab and we were able to rationalize that hydronium, but not hydroxide, is slightly enriched at the surface for two reasons. First, because the hydrogen bond acceptance capacity of hydronium is weaker than water and it is more favorable to have the hydronium oxygen on the surface. Second, hydroxide ions are expelled from the surface of the droplets, due to the entropy being lower when a hydroxide ion is hydrated on the surface. As a result, the water dissociation constant pK(w) increases slightly near the surface. The results are corroborated by calculations of surface tension of NaOH solutions that are in reasonable agreement with the experiment. The structural and thermodynamic interpretation of hydronium and hydroxide hydration provided by these calculations opens the route to a better understanding of atmospheric and surface chemistry.
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| 9. |
- Hub, Jochen S., et al.
(författare)
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Voltage-Regulated Water Flux through Aquaporin Channels In Silico
- 2010
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Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 99:12, s. L97-L99
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Tidskriftsartikel (refereegranskat)abstract
- Aquaporins (AQPs) facilitate the passive flux of water across biological membranes in response to an osmotic pressure. A number of AQPs, for instance in plants and yeast, have been proposed to be regulated by phosphorylation, cation concentration, pH change, or membrane-mediated mechanical stress. Here we report an extensive set of molecular dynamics simulations of AQP1 and AQP4 subject to large membrane potentials in the range of +/- 1.5 V, suggesting that AQPs may in addition be regulated by an electrostatic potential. As the regulatory mechanism we identified the relative population of two different states of the conserved arginine in the aromatic/arginine constriction region. A positive membrane potential was found to stabilize the arginine in an up-state, which allows rapid water flux, whereas a negative potential favors a down-state, which reduces the single-channel water permeability.
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| 10. |
- Malmerberg, Erik, 1980, et al.
(författare)
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Time-Resolved WAXS Reveals Accelerated Conformational Changes in Iodoretinal-Substituted Proteorhodopsin.
- 2011
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Ingår i: Biophysical journal. - : Elsevier BV. - 1542-0086 .- 0006-3495. ; 101:6, s. 1345-53
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Tidskriftsartikel (refereegranskat)abstract
- Time-resolved wide-angle x-ray scattering (TR-WAXS) is an emerging biophysical method which probes protein conformational changes with time. Here we present a comparative TR-WAXS study of native green-absorbing proteorhodopsin (pR) from SAR86 and a halogenated derivative for which the retinal chromophore has been replaced with 13-desmethyl-13-iodoretinal (13-I-pR). Transient absorption spectroscopy differences show that the 13-I-pR photocycle is both accelerated and displays more complex kinetics than native pR. TR-WAXS difference data also reveal that protein structural changes rise and decay an order-of-magnitude more rapidly for 13-I-pR than native pR. Despite these differences, the amplitude andnature of the observed helical motions are not significantly affected by the substitution of the retinal's C-20 methyl group with an iodine atom. Molecular dynamics simulations indicate that a significant increase in free energy is associated with the 13-cis conformation of 13-I-pR, consistent with our observation that the transient 13-I-pR conformational state is reached more rapidly. We conclude that although the conformational trajectory is accelerated, the major transient conformation of pR is unaffected by the substitution of an iodinated retinal chromophore.
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