Increasing evidence indicates that oligomeric protein assemblies may represent the molecular species responsible for cytotoxicity in a range of neurological disorders including Alzheimer and Parkinson diseases. We use all-atom computer simulations to reveal that the process of oligomerization can be divided into two steps. The first is characterised by a hydrophobic coalescence resulting in the formation of molten oligomers in which hydrophobic residues are sequestered away from the solvent. In the second step, the oligomers undergo a process of reorganisation driven by interchain hydrogen bonding interactions that induce the formation of β sheet rich assemblies in which hydrophobic groups can become exposed. Our results show that the process of aggregation into either ordered or amorphous species is largely determined by a competition between the hydrophobicity of the amino acid sequence and the tendency of polypeptide chains to form arrays of hydrogen bonds. We discuss how the increase in solvent-exposed hydrophobic surface resulting from such a competition offers an explanation for recent observations concerning the cytotoxicity of oligomeric species formed prior to mature amyloid fibrils.
We extend PRIME, an intermediate-resolution protein model previously used in simulations of the aggregation of polyalanine and polyglutamine, to the description of the geometry and energetics of peptides containing all twenty amino acid residues. The 20 amino acid side chains are classified into 14 groups according to their hydrophobicity, polarity, size, charge and potential for side chain hydrogen bonding. The parameters for extended PRIME, called PRIME 20, include hydrogenbonding energies, side-chain interaction range and energy, and excluded volume. The parameters are obtained by applying a perceptron-learning algorithm and a modified stochastic learning algorithm that optimizes the energy gap between 711 known native states from the PDB and decoy structures generated by gapless threading. The number of independent pair-interaction parameters is chosen to be small enough to be physically meaningful yet large enough to give reasonably accurate results in discriminating decoys from native structures. The most physically meaningful results are obtained with 19 energy parameters.
We calculate high-temperature graph expansions for the Ising spin glass model with 4 symmetric random distribution functions for its nearest neighbor interaction constants J ij . Series for the Edwards-Anderson susceptibility χ EA are obtained to order 13 in the expansion variable (J/(k B T )) 2 for the general d-dimensional hyper-cubic lattice, where the parameter J determines the width of the distributions. We explain in detail how the expansions are calculated. The analysis, using the Dlog-Padé approximation and the techniques known as M1 and M2, leads to estimates for the critical threshold (J/(k B T c )) 2 and for the critical exponent γ in dimensions 4, 5, 7 and 8 for all the distribution functions. In each dimension the values for γ agree, within their uncertainty margins, with a common value for the different distributions, thus confirming universality.
Macrolide-specific efflux pump MacAB-TolC has been identified in diverse Gram-negative bacteria including Escherichia coli. The inner membrane transporter MacB requires the outer membrane factor TolC and the periplasmic adaptor protein MacA to form a functional tripartite complex. In this study, we used a chimeric protein containing the tip region of the TolC ␣-barrel to investigate the role of the TolC ␣-barrel tip region with regard to its interaction with MacA. The chimeric protein formed a stable complex with MacA, and the complex formation was abolished by substitution at the functionally essential residues located at the MacA ␣-helical tip region. Electron microscopic study delineated that this complex was made by tip-to-tip interaction between the tip regions of the ␣-barrels of TolC and MacA, which correlated well with the TolC and MacA complex calculated by molecular dynamics. Taken together, our results demonstrate that the MacA hexamer interacts with TolC in a tip-to-tip manner, and implies the manner by which MacA induces opening of the TolC channel.Drug resistance of microbial pathogens presents an increasing threat to public health (1). In Gram-negative pathogens, high levels of intrinsic or acquired drug resistance are conferred by three-component multidrug efflux pumps, which are composed of the inner membrane transporter, the outer membrane factor (OMF), and the periplasmic membrane fusion protein (MFP) 4 (2-5). These tripartite complexes span the entire twomembrane envelope of Gram-negative bacteria and expel various molecules into the medium, utilizing a proton gradient or ATP hydrolysis. The inner membrane transporters belong to one of three structurally dissimilar superfamilies of proteins: resistance-nodulation-cell division (RND), ATP-binding cassette (ABC), or major facilitator. The inner membrane transporters expel the substrates through the central channel of the OMF, as exemplified by Escherichia coli TolC, which spans the outer membrane (6). The MFP, which connects the other two components in the periplasm, is also essential for the function of the efflux pump.In E. coli, AcrAB-TolC acts as a major multidrug efflux pump (7-9), where AcrB is the RND-type inner membrane transporter and AcrA belongs to MFP. The homotrimeric TolC is embedded in the outer membrane and continues ϳ100 Å into the periplasmic space as an ␣-barrel composed of six ␣-hairpins that form the wall of a 35-Å inner-diameter cylindrical channel (10). The TolC channel is closed at the aperture end and the channel opening is induced only in the presence of the other components, the mechanism of which remains to be determined at the molecular level.The MacAB-TolC pump has been identified in E. coli; the inner membrane transporter MacB belongs to non-canonic ABC-type transporters (8,9,11,12), and MFP MacA shares structural similarity with AcrA (sequence similarity 44%) (13). Overproduction of MacAB results in increased resistance to the macrolide antibiotics in macrolide-susceptible AcrAB-deficient E. coli (8, 9, 11).The s...
Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimer's and Parkinson's. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 Aβ(16-22) peptides, following the trajectories in molecular detail from an initial random configuration to a final configuration of twisted protofilaments with cross-β-structure. We accomplish this by performing large-scale molecular-dynamics simulations based on an implicit-solvent, intermediate-resolution protein model, PRIME20. Structural details such as the intersheet distance, perfectly antiparallel β-strands, and interdigitating side chains analogous to a steric zipper interface are explained by and in agreement with experiment. Two characteristic fibrillization mechanisms - nucleation/templated growth and oligomeric merging/structural rearrangement - emerge depending on the temperature.
Discovering the mechanisms by which proteins aggregate into fibrils is an essential first step in understanding the molecular level processes underlying neurodegenerative diseases such as Alzheimer’s and Parkinson's. The goal of this work is to provide insights into the structural changes that characterize the kinetic pathways by which amyloid-β peptides convert from monomers to oligomers to fibrils. By applying discontinuous molecular dynamics simulations to PRIME20, a force field designed to capture the chemical and physical aspects of protein aggregation, we have been able to trace out the entire aggregation process for a system containing 8 Aβ17–42 peptides. We uncovered two fibrillization mechanisms that govern the structural conversion of Aβ17–42 peptides from disordered oligomers into protofilaments. The first mechanism is monomeric conversion templated by a U-shape oligomeric nucleus into U-shape protofilament. The second mechanism involves a long-lived and on-pathway metastable oligomer with S-shape chains, having a C-terminal turn, en route to the final U-shape protofilament. Oligomers with this C-terminal turn have been regarded in recent experiments as a major contributing element to cell toxicity in Alzheimer’s disease. The internal structures of the U-shape protofilaments from our PRIME20/DMD simulation agree well with those from solid state NMR experiments. The approach presented here offers a simple molecular-level framework to describe protein aggregation in general and to visualize the kinetic evolution of a putative toxic element in Alzheimer’s disease in particular.
We study the site and bond quantum percolation model on the two-dimensional square lattice using series expansion in the low concentration limit. We calculate series for the averages of P ij r k ij Tij(E), where Tij(E) is the transmission coefficient between sites i and j, for k = 0, 1, . . . , 5 and for several values of the energy E near the center of the band. In the bond case the series are of order p 14 in the concentration p (some of those have been formerly available to order p 10 ) and in the site case of order p 16 . The analysis, using the Dlog-Padé approximation and the techniques known as M1 and M2, shows clear evidence for a delocalization transition (from exponentially localized to extended or power-law-decaying states) at an energy-dependent threshold pq(E) in the range pc < pq(E) < 1, confirming previous results (e.g. pq(0.05) = 0.625 ± 0.025 and 0.740 ± 0.025 for bond and site percolation) but in contrast with the Anderson model. The divergence of the series for different k is characterized by a constant gap exponent, which is identified as the localization length exponent ν from a general scaling assumption. We obtain estimates of ν = 0.57 ± 0.10. These values violate the bound ν ≥ 2/d of Chayes et al.
We investigate the fibrillization process for amyloid tau fragment peptides (VQIVYK) by applying the discontinuous molecular dynamics method to a system of 48 VQIVYK peptides modeled using a new protein model/force field, PRIME20. The aim of the article is to ascertain which factors are most important in determining whether or not a peptide system forms perfect coherent fibrillar structures. Two different directional criteria are used to determine when a hydrogen bond occurs: the original H-bond constraints and a parallel preference H-bond constraint that imparts a slight bias towards the formation of parallel versus antiparallel strands in a b-sheet. Under the original H-bond constraints, the resulting fibrillar structures contain a mixture of parallel and antiparallel pairs of strands within each b-sheet over the whole fibrillization temperature range. Under the parallel preference H-bond constraints, the b-sheets within the fibrillar structures are more likely to be parallel and indeed become perfectly parallel, consistent with X-ray crystallography, at a high temperature slightly below the fibrillization temperature. The high temperature environment encourages the formation of perfect fibril structures by providing enough time and space for peptides to rearrange during the aggregation process. There are two different kinetic mechanisms, template assembly with monomer addition at high temperature and merging/ rearrangement without monomer addition at low temperature, which lead to significant differences in the final fibrillar structure. This suggests that the diverse fibril morphologies generally observed in vitro depend more on environmental conditions than has heretofore been appreciated.
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