The Amyloid-beta protein is related to Alzheimer’s disease, and various experiments have shown that oligomers as small as the dimer are cytotoxic. Two alloforms are mainly produced: Aβ1–40 and ...Aβ1–42. They have very different oligomer distributions, and it was recently suggested, from experimental studies, that this variation may originate from structural differences in their dimer structures. Little structural information is available on the Aβ dimer, however, and to complement experimental observations, we simulated the folding of the wild-type Aβ1–40 and Aβ1–42 dimers as well as the mutated Aβ1–40(D23N) dimer using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics. The D23N variant impedes the salt-bridge formation between D23 and K28 seen in the wild-type Aβ, leading to very different fibrillation properties and final amyloid fibrils. Our results show that the Aβ1–42 dimer has a higher propensity than the Aβ1–40 dimer to form β-strands at the central hydrophobic core (residues 17–21) and at the C-terminal (residues 30–42), which are two segments crucial to the oligomerization of Aβ. The free energy landscape of the Aβ1–42 dimer is also broader and more complex than that of the Aβ1–40 dimer. Interestingly, D23N also impacts the free energy landscape by increasing the population of configurations with higher β-strand propensities when compared against Aβ40. In addition, while Aβ1–40(D23N) displays a higher β-strand propensity at the C-terminal, its solvent accessibility does not change with respect to the wild-type sequence. Overall, our results show the strong impact of the two amino acids Ile41-Ala42 and the salt-bridge D23–K28 on the folding of the Aβ dimer.
We study the role of temperature on the structure of pure polymer brushes and their mixture with attractive nanoparticles in flat and cylindrical geometries. It has previously been established that ...the addition of such nanoparticles causes the polymer brush to collapse and the intensity of the collapse depends on the attraction strength, the nanoparticle diameter, and the grafting density. In this work, we carry out molecular dynamics simulation under good solvent conditions to show how the collapse transition is affected by the temperature, for both plane grafted and inside-cylinder grafted brushes. We first examine the pure brush morphology and verify that the brush height is insensitive to temperature changes in both planar and cylindrical geometries, as expected for a polymer brush in a good solvent. On the other hand, for both system geometries, the brush structure in the presence of attractive nanoparticles is quite responsive to temperature changes. Generally speaking, for a given nanoparticle concentration, increasing the temperature causes the brush height to increase. A brush which contracts when nanoparticles are added eventually swells beyond its pure brush height as the system temperature is increased. The combination of two easily controlled external parameters, namely, concentration of nanoparticles in solution and temperature, allows for sensitive and reversible adjustment of the polymer brush height, a feature which could be exploited in designing smart polymer devices.
The loss of the insulin-producing β-cells in the pancreatic islets of Langerhans, responsible for type-II diabetes, is associated with islet amyloid deposits. The main component of these deposits is ...the amyloid fibrils formed by the 37-residue human islet amyloid polypeptide (hIAPP also known as amylin). Although the fibrils are well characterized by cross β structure, the structure of the transient oligomers formed in the early stage of aggregation remains elusive. In this study, we apply the Hamiltonian-temperature replica exchange molecular dynamics to characterize the structure and thermodynamics of a full-length hIAPP dimer in both the presence and the absence of the Cys2−Cys7 disulfide bond. We compare these results with those obtained on the monomeric and dimeric forms of rat IAPP (rIAPP) with a disulfide bridge which differ from the hIAPP by 6 amino acids in the C-terminal region, but it is unable to form fibrils. Using a coarse-grained protein force field (OPEPthe Optimized Potential for Efficient peptide structure Prediction) running for a total of 10−28 μs per system studied, we show that sequences sample α-helical structure in the N-terminal region but that the length of this secondary element is shorter and less stable for the chains without the disulfide bridge (residues 5−16 for hIAPP with the bridge vs 10−16 for hIAPP without the bridge). This α-helix is known to be an important transient stage in the formation of oligomers. In the C-terminal, the amyloidogenic region of hIAPP, β-strands are seen for residues 17−26 and 30−35. On the contrary, no significant β-sheet content in the C-terminal is observed for either the monomeric or the dimeric rIAPP. These numerical results are fully consistent with recent experimental findings that the N-terminal residues are not part of the fibril by forming α-helical structure but rather play a significant role in stabilizing the amyloidogenic region available for the fibrillation.
The general mechanism of calcium-triggered chemical transmitter release from neuronal synapses has been intensely studied, is well-known, and highly conserved between species and synapses across the ...nervous system. However, the structural and functional details within each transmitter release site (or active zone) are difficult to study in living tissue using current experimental approaches owing to the small spatial compartment within the synapse where exocytosis occurs with a very rapid time course. Therefore, computer simulations offer the opportunity to explore these microphysiological environments of the synapse at nanometer spatial scales and on a sub-microsecond timescale. Because biological reactions and physiological processes at synapses occur under conditions where stochastic behavior is dominant, simulation approaches must be driven by such stochastic processes. MCell provides a powerful simulation approach that employs particle-based stochastic simulation tools to study presynaptic processes in realistic and complex (3D) geometries using optimized Monte Carlo algorithms to track finite numbers of molecules as they diffuse and interact in a complex cellular space with other molecules in solution and on surfaces (representing membranes, channels and binding sites). In this review we discuss MCell-based spatially realistic models of the mammalian and frog neuromuscular active zones that were developed to study presynaptic mechanisms that control transmitter release. In particular, these models focus on the role of presynaptic voltage-gated calcium channels, calcium sensors that control the probability of synaptic vesicle fusion, and the effects of action potential waveform shape on presynaptic calcium entry. With the development of these models, they can now be used in the future to predict disease-induced changes to the active zone, and the effects of candidate therapeutic approaches.
Current approaches aimed at determining the free energy surface of all-atom medium-size proteins in explicit solvent are slow and are not sufficient to converge to equilibrium properties. To ensure a ...proper sampling of the configurational space, it is preferable to use reduced representations such as implicit solvent and/or coarse-grained protein models, which are much lighter computationally. Each model must be verified, however, to ensure that it can recover experimental structures and thermodynamics. Here we test the coarse-grained implicit solvent OPEP model with replica exchange molecular dynamics (REMD) on six peptides ranging in length from 10 to 28 residues: two alanine-based peptides, the second β-hairpin from protein G, the Trp-cage and zinc-finger motif, and a dimer of a coiled coil peptide. We show that REMD-OPEP recovers the proper thermodynamics of the systems studied, with accurate structural description of the β-hairpin and Trp-cage peptides (within 1−2 Å from experiments). The light computational burden of REMD-OPEP, which enables us to generate many hundred nanoseconds at each temperature and fully assess convergence to equilibrium ensemble, opens the door to the determination of the free energy surface of larger proteins and assemblies.
Calculation of Iron Transport through Human H‑chain Ferritin Laghaei, Rozita; Kowallis, William; Evans, Deborah G ...
The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory,
09/2014, Letnik:
118, Številka:
35
Journal Article
Recenzirano
Influx of ferrous ions from the cytoplasm through 3-fold pores in the shell of ferritin protein is computed using a 3-dimensional Poisson–Nernst–Planck electrodiffusion model, with inputs such as the ...pore structure and the diffusivity profile of permeant Fe2+ ions extracted from all-atom molecular dynamics (MD) simulations. These calculations successfully reproduce experimental estimates of the transit time of Fe2+ through the ferritin coat, which is on the millisecond time scale and hence much too long to be directly simulated via all-atom MD. This is also much longer than the typical time scale for ion transit in standard membrane spanning ion channels whose pores bear structural similarity to that of the 3-fold ferritin pore. The slow time scale for Fe2+ transport through ferritin pores is traced to two features that distinguish the ferritin pore system from standard ion channels, namely, (i) very low concentration of cytoplasmic Fe2+ under physiological conditions and (ii) very small internal diffusion coefficients for ions inside the ferritin pore resulting from factors that include the divalent nature of Fe2+ and two rings of negatively charged amino acids surrounding a narrow geometric obstruction within the ferritin pore interior.
The shear viscosity formula derived by the density fluctuation theory in previous papers is computed for argon, krypton, and methane by using the self-diffusion coefficients derived in the modified ...free volume theory with the help of the generic van der Waals equation of state. In the temperature regime near or above the critical temperature, the density dependence of the shear viscosity can be accounted for by ab initio calculations with the self-diffusion coefficients provided by the modified free volume theory if the minimum (critical) free volume is set equal to the molecular volume and the volume overlap parameter (α) is taken about unity in the expression for the self-diffusion coefficient. In the subcritical temperature regime, if the density fluctuation range parameter is chosen appropriately at a temperature, then the resulting expression for the shear viscosity can well account for its density and temperature dependence over the ranges of density and temperature experimentally studied. In the sense that once the density fluctuation range is fixed at a temperature, the theory can account for the experimental data at other subcritical temperatures on the basis of the intermolecular force only; the theory is predictive even in the subcritical regime of temperature. Theory is successfully tested in comparison with experimental data for self-diffusion coefficients and shear viscosity for argon, krypton, and methane.
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