The molecular mechanism and energetics of the translocation of arginine-rich, cell-penetrating peptides through membranes are still under debate. One possible mechanism involves the formation of a ...water pore in the membrane such that the hydrophilic residues of the peptide are solvated throughout the translocating process. In this work, employing two different order parameters, we calculate the free energies of translocating a cyclic Arg9 peptide into a lipid bilayer along one path that involves a water-pore formation and another path that does not form a separate pore. The free-energy barrier of translocating the peptide along a pore path is 80 kJ/mol lower than along a pore-free path. This suggests that the peptide translocation is more likely associated with a water-pore formation.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Though urea is commonly used to denature proteins, the molecular mechanism of its denaturing ability is still a subject of considerable debate. Previous molecular dynamics simulation studies have ...sought to elucidate the mechanism of urea denaturation by focusing on the pathway of denaturation rather than examining the effect of urea on the folding/unfolding equilibrium, which is commonly measured in experiment. Here we report the reversible folding/unfolding equilibrium of Trp-cage miniprotein in the presence of urea, over a broad range of urea concentrations, using all-atom Replica exchange MD simulations. The simulations capture the experimentally observed linear dependence of unfolding free energy on urea concentration. We find that the denaturation is driven by favorable direct interaction of urea with the protein through both electrostatic and van der Waals forces and quantify their contribution. Though the magnitude of direct electrostatic interaction of urea is larger than van der Waals, the difference between unfolded and folded ensembles is dominated by the van der Waals interaction. We also find that hydrogen bonding of urea to the peptide backbone does not play a dominant role in denaturation. The unfolded ensemble sampled depends on urea concentration, with greater urea concentration favoring conformations with greater solvent exposure. The m-value is predicted to increase with temperature and more strongly so with pressure.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Accurate force field parameters for ions are essential for meaningful simulation studies of proteins and nucleic acids. Currently accepted models of ions, especially for divalent ions, do not ...necessarily reproduce the right physiological behavior of Ca2+ and Mg2+ ions. Saxena and Sept (J. Chem. Theor. Comput. 2013, 9, 3538–3542) described a model, called the multisite-ion model, where instead of treating the ions as an isolated sphere, the charge was split into multiple sites with partial charge. This model provided accurate inner shell coordination of the ion with biomolecules and predicted better free energies for proteins and nucleic acids. Here, we expand and refine the multisite model to describe the behavior of divalent ions in concentrated MgCl2 and CaCl2 electrolyte solutions, eliminating the unusual ion–ion pairing and clustering of ions which occurred in the original model. We calibrate and improve the parameters of the multisite model by matching the osmotic pressure of concentrated solutions of MgCl2 to the experimental values and then use these parameters to test the behavior of CaCl2 solutions. We find that the concentrated solutions of both divalent ions exhibit the experimentally observed behavior with correct osmotic pressure, the presence of solvent separated ion pairs instead of direct ion pairs, and no aggregation of ions. The improved multisite model for (Mg2+ and Ca2+) can be used in classical simulations of biomolecules at physiologically relevant salt concentrations.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
G-protein-coupled receptors are eukaryotic membrane proteins with broad biological and pharmacological relevance. Like all membrane-embedded proteins, their location and orientation are influenced by ...lipids, which can also impact protein function via specific interactions. Extensive simulations totaling 0.25 ms reveal a process in which phospholipids from the membrane’s cytosolic leaflet enter the empty G-protein binding site of an activated β2 adrenergic receptor and form salt-bridge interactions that inhibit ionic lock formation and prolong active-state residency. Simulations of the receptor embedded in an anionic membrane show increased lipid binding, providing a molecular mechanism for the experimental observation that anionic lipids can enhance receptor activity. Conservation of the arginine component of the ionic lock among Rhodopsin-like G-protein-coupled receptors suggests that intracellular lipid ingression between receptor helices H6 and H7 may be a general mechanism for active-state stabilization.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Urea is an important organic cosolute with implications in maintaining osmotic stress in cells and differentially stabilizing ensembles of folded biomolecules. We report an equilibrium study of ...urea-induced denaturation of a hyperstable RNA tetraloop through unbiased replica exchange molecular dynamics. We find that, in addition to destabilizing the folded state, urea smooths the RNA free energy landscape by destabilizing specific configurations, and forming favorable interactions with RNA nucleobases. A linear concentration-dependence of the free energy (m-value) is observed, in agreement with the results of other RNA hairpins and proteins. Additionally, analysis of the hydrogen-bonding and stacking interactions within RNA primarily show temperature-dependence, while interactions between RNA and urea primarily show concentration-dependence. Our findings provide valuable insight into the effects of urea on RNA folding and describe the thermodynamics of a basic RNA hairpin as a function of solution chemistry.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Urea is a commonly used protein denaturant, and it is of great interest to determine its interaction with various protein groups to elucidate the molecular basis of its effect on protein stability. ...Using the Trp-cage miniprotein as a model system, we report what we believe to be the first computation of changes in the preferential interaction coefficient of the protein upon urea denaturation from molecular-dynamics simulations and examine the contributions from the backbone and the side-chain groups. The preferential interaction is obtained from reversible folding/unfolding replica exchange molecular-dynamics simulations of Trp-cage in presence of urea, over a wide range of urea concentration. The increase in preferential interaction upon unfolding is dominated by the side-chain contribution, rather than the backbone. Similar trends are observed in simulations using two different force fields, Amber94 and Amber99sb, for the protein. The magnitudes of the side-chain and backbone contributions differ in the two force fields, despite containing identical protein-solvent interaction terms. The differences arise from the unfolded ensembles sampled, with Amber99sb favoring conformations with larger surface area and lower helical content. These results emphasize the importance of the side-chain interactions with urea in protein denaturation, and highlight the dependence of the computed driving forces on the unfolded ensemble sampled.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Amyloid β (Aβ) peptides are a primary component of fibrils and oligomers implicated in the etiology of Alzheimer's disease (AD). However, the intrinsic flexibility of these peptides has frustrated ...efforts to investigate the secondary and tertiary structure of Aβ monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of Aβ aggregation. In this work, de novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale are used to characterize the structural ensembles of Aβ42, Aβ40, and M35-oxidized Aβ42, three physiologically relevant isoforms with substantially different aggregation properties. J-coupling data calculated from the REMD trajectories were compared to corresponding NMR-derived values acquired through two different pulse sequences, revealing that all simulations converge on the order of hundreds of nanoseconds-per-replica toward ensembles that yield good agreement with experiment. Though all three Aβ species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C-terminus are antiparallel β-hairpins between L17–A21, A30–L36, and V39–I41, similar to oligomer and fibril intrapeptide models that expose these hydrophobic side chains to solvent and may serve as hotspots for self-association. Compared to reduced Aβ42, the absence of a second β-hairpin in Aβ40 and the sampling of alternate β topologies by M35-oxidized Aβ42 may explain the reduced aggregation rates of these forms. A persistent V24–K28 bend motif, observed in all three species, is stabilized by buried backbone to side-chain hydrogen bonds with D23 and a cross-region salt bridge between E22 and K28, highlighting the role of the familial AD-linked E22 and D23 residues in Aβ monomer folding. These characterizations help illustrate the conformational landscapes of Aβ monomers at atomic resolution and provide insight into the early stages of Aβ aggregation pathways.
Display omitted
•Ensembles of Aβ42, Aβ40, and Aβ42-M35ox(S) monomers are characterized with REMD.•Validation through J-couplings is acquired with two different pulse sequences.•Structures similar to intrapeptide models of oligomers and fibrils are observed.•Sampling of different β topologies may explain variation in aggregation propensity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Premise
Of all orchid species described, 70% live on phorophytes. Trees offer a vital space with characteristics that influence the successful establishment and life cycle of orchids. Field inventory ...and distribution analysis suggest that phorophyte selection is biased to certain tree species that would serve as better hosts. Phorophyte bark is known as an important factor that influences this preference, but the chemical and physical properties of bark that contribute to creating a favorable space for orchids are still poorly understood. In this work, the effect of bark physical characteristics on phorophyte preference of tropical orchids was studied.
Methods
Orchids and their phorophytes were counted and identified along transects inside two natural reserves in Southeast Mexico. A rhytidome classification was used to describe the bark decoration patterns of the phorophytes. To quantify bark fissuring, we developed a new protocol based on image processing of light micrographs using free‐access software. Bark topology characterization was complemented with scanning electronic microscopy. Maximum and minimum water content was also determined.
Results
Analyses of bark decorations and bark fissuring were not enough to explain the preference found for some tropical trees. In contrast, a positive relationship was found among water‐storage capacity, bark porosity, and phorophyte preference. The host trees preferred by most orchids have bark with higher pore density and higher water retention after draining.
Conclusions
Unexpectedly, the phorophytes preferred by orchids are not those with more fissured bark but those with a higher ability to retain minimum water content after draining, which is a bark property positively correlated with higher pore density. Our data indicate that the bark microenvironment, determined by topology and water storage capacity, has a pivotal role in phorophyte specificity, a key factor that affects orchid diversity and distribution in the world.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The lateral heterogeneity of cellular membranes plays an important role in many biological functions such as signaling and regulating membrane proteins. This heterogeneity can result from ...preferential interactions between membrane components or interactions with membrane proteins. One major difficulty in molecular dynamics simulations aimed at studying the membrane heterogeneity is that lipids diffuse slowly and collectively in bilayers, and therefore, it is difficult to reach equilibrium in lateral organization in bilayer mixtures. Here, we propose the use of the replica exchange with solute tempering (REST) approach to accelerate lateral relaxation in heterogeneous bilayers. REST is based on the replica exchange method but tempers only the solute, leaving the temperature of the solvent fixed. Since the number of replicas in REST scales approximately only with the degrees of freedom in the solute, REST enables us to enhance the configuration sampling of lipid bilayers with fewer replicas, in comparison with the temperature replica exchange molecular dynamics simulation (T-REMD) where the number of replicas scales with the degrees of freedom of the entire system. We apply the REST method to a cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayer mixture and find that the lateral distribution functions of all molecular pair types converge much faster than in the standard MD simulation. The relative diffusion rate between molecules in REST is, on average, an order of magnitude faster than in the standard MD simulation. Although REST was initially proposed to study protein folding and its efficiency in protein folding is still under debate, we find a unique application of REST to accelerate lateral equilibration in mixed lipid membranes and suggest a promising way to probe membrane lateral heterogeneity through molecular dynamics simulation.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Agricultural landscapes cover >60% of terrestrial landscapes. While biodiversity conservation and crop productivity have been seen as mutually exclusive options for a long time, recent research ...suggests that agricultural landscapes represent significant opportunities for biodiversity conservation outside of traditional protected areas.
Here, we use a unique dataset that includes annual monitoring of 12,300 permanent 25‐ha plots over two decades across Spain to assess how agricultural landscapes are changing over time. We focus particularly on landscape composition and configuration variables such as the diversity of crops grown within a landscape, average plot size or the cover of natural habitats and assess how changes to these variables affect the ability of agricultural landscapes to ensure high yields.
We find potential synergistic strategies that are good for biodiversity conservation and can also lead to increasing crop yields. Specifically, we find that management practices that favour increasing biodiversity values such as maintaining small field sizes and high crop richness values at the landscape scale actually led to the greatest average yield values across 54 crops, 41% of which depend on pollinator activity for reproduction.
Policy implications: While our analysis does not factor in economic costs and benefits, we show that synergy scenarios that are good for biodiversity conservation and crop productivity are possible, yet not as widespread as they could be.
Resumen
Los paisajes agrícolas cubren >60% de las zonas terrestres. Aunque tradicionalmente la conservación de la biodiversidad y la producción agrícola se han considerado mutuamente excluyentes, recientes investigaciones sugieren que los paisajes agrícolas brindan oportunidades significativas para la conservación de la biodiversidad fuera de las áreas protegidas tradicionales.
En este estudio utilizamos una base de datos única que incluye un monitoreo anual de 12.300 parcelas permanentes de 25 hectáreas a lo largo de dos décadas, en España, para evaluar cómo están cambiando a lo largo del tiempo los paisajes agrícolas. Atendiendo a variables que definen la composición y configuración del paisaje, tales como la diversidad de cultivos que se plantan en una zona, el tamaño medio de los campos agrícolas o la cobertura de hábitats naturales; evaluamos cómo los cambios de dichas variables han podido afectar a la producción agrícola en estos paisajes.
Hallamos estrategias de manejo que muestran potenciales sinergias entre la conservación de la biodiversidad y el incremento en los rendimientos de los cultivos con el tiempo. En concreto, detectamos que prácticas de manejo que favorecen el aumento de la biodiversidad como mantener campos de cultivo pequeños y valores de diversidad de cultivos altos, también supusieron incrementos en el rendimiento de 54 cultivos, 41% de los cuales dependen de los polinizadores para la producción de frutos.
Implicaciones políticas: Aunque nuestro análisis no incluye factores económicos, demostramos que escenarios en los que existen sinergias entre la conservación de la biodiversidad y el aumento de rendimientos de cultivos son posibles, aunque por ahora no están tan extendidos como podrían.
While our analysis does not factor in economic costs and benefits, we show that synergy scenarios that are good for biodiversity conservation and crop productivity are possible, yet not as widespread as they could be.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
