81 research outputs found
Role of electrostatic interactions in amyloid beta-protein (Abeta) oligomer formation: A discrete molecular dynamics study
Pathological folding and oligomer formation of the amyloid beta-protein
(Abeta) are widely perceived as central to Alzheimer's disease (AD).
Experimental approaches to study Abeta self-assembly are problematic, because
most relevant aggregates are quasi-stable and inhomogeneous. We apply a
discrete molecular dynamics (DMD) approach combined with a four-bead protein
model to study oligomer formation of the amyloid beta-protein (Abeta). We
address the differences between the two most common Abeta alloforms, Abeta40
and Abeta42, which oligomerize differently in vitro. We study how the presence
of electrostatic interactions (EIs) between pairs of charged amino acids
affects Abeta40 and Abeta42 oligomer formation. Our results indicate that EIs
promote formation of larger oligomers in both Abeta40 and Abeta42. The Abeta40
size distribution remains unimodal, whereas the Abeta42 distribution is
trimodal, as observed experimentally. Abeta42 folded structure is characterized
by a turn in the C-terminus that is not present in Abeta40. We show that the
same C-terminal region is also responsible for the strongest intermolecular
contacts in Abeta42 pentamers and larger oligomers. Our results suggest that
this C-terminal region plays a key role in the formation of Abeta42 oligomers
and the relative importance of this region increases in the presence of EIs.
These results suggest that inhibitors targeting the C-terminal region of
Abeta42 oligomers may be able to prevent oligomer formation or structurally
modify the assemblies to reduce their toxicity.Comment: Accepted for publication at Biophysical Journa
hA molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization
Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(35)-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD
Hydrophobic and ionic-interactions in bulk and confined water with implications for collapse and folding of proteins
Water and water-mediated interactions determine thermodynamic and kinetics of
protein folding, protein aggregation and self-assembly in confined spaces. To
obtain insights into the role of water in the context of folding problems, we
describe computer simulations of a few related model systems. The dynamics of
collapse of eicosane shows that upon expulsion of water the linear hydrocarbon
chain adopts an ordered helical hairpin structure with 1.5 turns. The structure
of dimer of eicosane molecules has two well ordered helical hairpins that are
stacked perpendicular to each other. As a prelude to studying folding in
confined spaces we used simulations to understand changes in hydrophobic and
ionic interactions in nano droplets. Solvation of hydrophobic and charged
species change drastically in nano water droplets. Hydrophobic species are
localized at the boundary. The tendency of ions to be at the boundary where
water density is low increases as the charge density decreases. Interaction
between hydrophobic, polar, and charged residue are also profoundly altered in
confined spaces. Using the results of computer simulations and accounting for
loss of chain entropy upon confinement we argue and then demonstrate, using
simulations in explicit water, that ordered states of generic amphiphilic
peptide sequences should be stabilized in cylindrical nanopores
Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide
Understanding the influence of macromolecular crowding and nanoparticles on
the formation of in-register -sheets, the primary structural component
of amyloid fibrils, is a first step towards describing \emph{in vivo} protein
aggregation and interactions between synthetic materials and proteins. Using
all atom molecular simulations in implicit solvent we illustrate the effects of
nanoparticle size, shape, and volume fraction on oligomer formation of an
amyloidogenic peptide from the transthyretin protein. Surprisingly, we find
that inert spherical crowding particles destabilize in-register -sheets
formed by dimers while stabilizing -sheets comprised of trimers and
tetramers. As the radius of the nanoparticle increases crowding effects
decrease, implying smaller crowding particles have the largest influence on the
earliest amyloid species. We explain these results using a theory based on the
depletion effect. Finally, we show that spherocylindrical crowders destabilize
the ordered -sheet dimer to a greater extent than spherical crowders,
which underscores the influence of nanoparticle shape on protein aggregation
A Condensation-Ordering Mechanism in Nanoparticle-Catalyzed Peptide Aggregation
Nanoparticles introduced in living cells are capable of strongly promoting
the aggregation of peptides and proteins. We use here molecular dynamics
simulations to characterise in detail the process by which nanoparticle
surfaces catalyse the self- assembly of peptides into fibrillar structures. The
simulation of a system of hundreds of peptides over the millisecond timescale
enables us to show that the mechanism of aggregation involves a first phase in
which small structurally disordered oligomers assemble onto the nanoparticle
and a second phase in which they evolve into highly ordered beta-sheets as
their size increases
Behavioural cloning of teachers for automatic homework selection
© Springer Nature Switzerland AG 2019. We describe a machine-learning system for supporting teachers through the selection of homework assignments. Our system uses behavioural cloning of teacher activity to generate personalised homework assignments for students. Classroom use is then supported through additional mechanisms to combine these predictions into group assignments. We train and evaluate our system against 50,065 homework assignments collected over two years by the Isaac Physics platform. We use baseline policies incorporating expert curriculum knowledge for evaluation and find that our technique improves on the strongest baseline policy by 18.5% in Year 1 and by 13.3% in Year 2.Cambridge Assessmen
Molecular Dynamics Studies of the Nucleoprotein of Influenza A Virus: Role of the Protein Flexibility in RNA Binding
The influenza viruses contain a segmented, negative stranded RNA genome. Each RNA segment is covered by multiple copies of the nucleoprotein (NP). X-ray structures have shown that NP contains well-structured domains juxtaposed with regions of missing electron densities corresponding to loops. In this study, we tested if these flexible loops gated or promoted RNA binding and RNA-induced oligomerization of NP. We first performed molecular dynamics simulations of wt NP monomer and trimer in comparison with the R361A protein mutated in the RNA binding groove, using the H1N1 NP as the initial structure. Calculation of the root-mean-square fluctuations highlighted the presence of two flexible loops in NP trimer: loop 1 (73–90), loop 2 (200–214). In NP, loops 1 and 2 formed a 10–15 Å-wide pinch giving access to the RNA binding groove. Loop 1 was stabilized by interactions with K113 of the adjacent β-sheet 1 (91–112) that interacted with the RNA grove (linker 360–373) via multiple hydrophobic contacts. In R361A, a salt bridge formed between E80 of loop 1 and R208 of loop 2 driven by hydrophobic contacts between L79 and W207, due to a decreased flexibility of loop 2 and loop 1 unfolding. Thus, RNA could not access its binding groove in R361A; accordingly, R361A had a much lower affinity for RNA than NP. Disruption of the E80-R208 interaction in the triple mutant R361A-E80A-E81A increased its RNA binding affinity and restored its oligomerization back to wt levels in contrast with impaired levels of R361A. Our data suggest that the flexibility of loops 1 and 2 is required for RNA sampling and binding which likely involve conformational change(s) of the nucleoprotein
Multiple pH Regime Molecular Dynamics Simulation for pK Calculations
Ionisation equilibria in proteins are influenced by conformational flexibility, which can in principle be accounted for by molecular dynamics simulation. One problem in this method is the bias arising from the fixed protonation state during the simulation. Its effect is mostly exhibited when the ionisation behaviour of the titratable groups is extrapolated to pH regions where the predetermined protonation state of the protein may not be statistically relevant, leading to conformational sampling that is not representative of the true state. In this work we consider a simple approach which can essentially reduce this problem. Three molecular dynamics structure sets are generated, each with a different protonation state of the protein molecule expected to be relevant at three pH regions, and pK calculations from the three sets are combined to predict pK over the entire pH range of interest. This multiple pH molecular dynamics approach was tested on the GCN4 leucine zipper, a protein for which a full data set of experimental data is available. The pK values were predicted with a mean deviation from the experimental data of 0.29 pH units, and with a precision of 0.13 pH units, evaluated on the basis of equivalent sites in the dimeric GCN4 leucine zipper
Formation and Growth of Oligomers: A Monte Carlo Study of an Amyloid Tau Fragment
Small oligomers formed early in the process of amyloid fibril formation may be the major toxic species in Alzheimer's disease. We investigate the early stages of amyloid aggregation for the tau fragment AcPHF6 (Ac-VQIVYK-NH2) using an implicit solvent all-atom model and extensive Monte Carlo simulations of 12, 24, and 36 chains. A variety of small metastable aggregates form and dissolve until an aggregate of a critical size and conformation arises. However, the stable oligomers, which are β-sheet-rich and feature many hydrophobic contacts, are not always growth-ready. The simulations indicate instead that these supercritical oligomers spend a lengthy period in equilibrium in which considerable reorganization takes place accompanied by exchange of chains with the solution. Growth competence of the stable oligomers correlates with the alignment of the strands in the β-sheets. The larger aggregates seen in our simulations are all composed of two twisted β-sheets, packed against each other with hydrophobic side chains at the sheet–sheet interface. These β-sandwiches show similarities with the proposed steric zipper structure for PHF6 fibrils but have a mixed parallel/antiparallel β-strand organization as opposed to the parallel organization found in experiments on fibrils. Interestingly, we find that the fraction of parallel β-sheet structure increases with aggregate size. We speculate that the reorganization of the β-sheets into parallel ones is an important rate-limiting step in the formation of PHF6 fibrils
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