120 research outputs found
Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates
The presence of oligomeric aggregates, which is often observed during the
process of amyloid formation, has recently attracted much attention since it
has been associated with neurodegenerative conditions such as Alzheimer's and
Parkinson's diseases. We provide a description of a sequence-indepedent
mechanism by which polypeptide chains aggregate by forming metastable
oligomeric intermediate states prior to converting into fibrillar structures.
Our results illustrate how the formation of ordered arrays of hydrogen bonds
drives the formation of beta-sheets within the disordered oligomeric aggregates
that form early under the effect of hydrophobic forces. Initially individual
beta-sheets form with random orientations, which subsequently tend to align
into protofilaments as their lengths increases. Our results suggest that
amyloid aggregation represents an example of the Ostwald step rule of first
order phase transitions by showing that ordered cross-beta structures emerge
preferentially from disordered compact dynamical intermediate assemblies.Comment: 14 pages, 4 figure
Integrity of H1 helix in prion protein revealed by molecular dynamic simulations to be especially vulnerable to changes in the relative orientation of H1 and its S1 flank
In the template-assistance model, normal prion protein (PrPC), the pathogenic
cause of prion diseases such as Creutzfeldt-Jakob (CJD) in human, Bovine
Spongiform Encephalopathy (BSE) in cow, and scrapie in sheep, converts to
infectious prion (PrPSc) through an autocatalytic process triggered by a
transient interaction between PrPC and PrPSc. Conventional studies suggest the
S1-H1-S2 region in PrPC to be the template of S1-S2 -sheet in PrPSc, and
the conformational conversion of PrPC into PrPSc may involve an unfolding of H1
in PrPC and its refolding into the -sheet in PrPSc. Here we conduct a
series of simulation experiments to test the idea of transient interaction of
the template-assistance model. We find that the integrity of H1 in PrPC is
vulnerable to a transient interaction that alters the native dihedral angles at
residue Asn, which connects the S1 flank to H1, but not to interactions
that alter the internal structure of the S1 flank, nor to those that alter the
relative orientation between H1 and the S2 flank.Comment: A major revision on statistical analysis method has been made. The
paper now has 23 pages, 11 figures. This work was presented at 2006 APS March
meeting session K29.0004 at Baltimore, MD, USA 3/13-17, 2006. This paper has
been accepted for pubcliation in European Biophysical Journal on Feb 2, 200
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
Recommended from our members
Arable weed seeds as indicators of regional cereal provenance: a case study from Iron Age and Roman central-southern Britain
The ability to provenance crop remains from archaeological sites remains an outstanding research question in archaeology. Archaeobotanists have previously identified the movement of cereals on the basis of regional variations in the presence of cereal grain, chaff and weed seeds (the consumer–producer debate), and weed seeds indicative of certain soil types, principally at Danebury hillfort. Whilst the former approach has been heavily criticised over the last decade, the qualitative methods of the latter have not been evaluated. The first interregional trade in cereals in Britain is currently dated to the Iron Age hillfort societies of the mid 1st millennium bc. Several centuries later, the development of urban settlements in the Late Iron Age and Roman period resulted in populations reliant on food which was produced elsewhere. Using the case study of central-southern Britain, centred on the oppidum (large fortified settlement) and civitas capital of Silchester, this paper presents the first regional quantitative analysis of arable weed seeds in order to identify the origin of the cereals consumed there. Analysis of the weed seeds which were present with the fine sieve by-products of the glume wheat Triticum spelta (spelt) shows that the weed floras of samples from diverse geological areas can be separated on the basis of the soil requirements of individual taxa. A preliminary finding is that, rather than being supplied with cereals from the wider landscape of the chalk region of the Hampshire Downs, the crops were grown close to Late Iron Age Silchester. The method presented here requires further high quality samples to evaluate this conclusion and other instances of cereal movement in the past
Probing the Flexibility of Large Conformational Changes in Protein Structures through Local Perturbations
Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate—the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP), which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of α-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen Receptor ligand-binding domain, the RIP deformation map is quite sparse except for one large conformational change involving Helix-12, which is the structural element that allosterically links ligand binding to receptor activation. RIP analysis has the potential to discover sites of functional conformational changes and the linchpin residues critical in determining these conformational states
Conformation Effects of CpG Methylation on Single-Stranded DNA Oligonucleotides: Analysis of the Opioid Peptide Dynorphin-Coding Sequences
Single-stranded DNA (ssDNA) is characterized by high conformational flexibility that allows these molecules to adopt a variety of conformations. Here we used native polyacrylamide gel electrophoresis (PAGE), circular dichroism (CD) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy to show that cytosine methylation at CpG sites affects the conformational flexibility of short ssDNA molecules. The CpG containing 37-nucleotide PDYN (prodynorphin) fragments were used as model molecules. The presence of secondary DNA structures was evident from differences in oligonucleotide mobilities on PAGE, from CD spectra, and from formation of A-T, G-C, and non-canonical G-T base pairs observed by NMR spectroscopy. The oligonucleotides displayed secondary structures at 4°C, and some also at 37°C. Methylation at CpG sites prompted sequence-dependent formation of novel conformations, or shifted the equilibrium between different existing ssDNA conformations. The effects of methylation on gel mobility and base pairing were comparable in strength to the effects induced by point mutations in the DNA sequences. The conformational effects of methylation may be relevant for epigenetic regulatory events in a chromatin context, including DNA-protein or DNA-DNA recognition in the course of gene transcription, and DNA replication and recombination when double-stranded DNA is unwinded to ssDNA
Intrinsic Determinants of Aβ12–24 pH-Dependent Self-Assembly Revealed by Combined Computational and Experimental Studies
The propensity of amyloid- (A) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, -sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A amyloid formation; it is highly prompted in the order of pH 5.02.98.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of -sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases
Theoretical study of the NLO responses of some natural and unnatural amino acids used as probe molecules
International audienceno abstrac
UnityMol: Interactive scientific visualization for integrative biology
International audienceno abstrac
- …