Amyloid beta-protein monomer structure: A computational and experimental study (original) (raw)
Related papers
Amyloid-β peptide structure in aqueous solution varies with fragment size
The Journal of chemical physics, 2011
Phase diagram of polypeptide chains JCP: BioChem. Phys. 5, 11B602 (2011) Effects of surface interactions on peptide aggregate morphology JCP: BioChem. Phys. 5, 08B624 (2011) Effects of surface interactions on peptide aggregate morphology J. Chem. Phys. 135, 085102 (2011) Does amino acid sequence determine the properties of A dimer? J. Chem. Phys. 135, 035103 (2011) Additional information on J. Chem. Phys.
Journal of Molecular Structure: THEOCHEM, 2001
The effect of the Ala-substitution, the N-and C-terminal capping and the presence of Ca 21 , Mg 21 and Zn 21 on the structure of amyloid peptide fragment, Ab(25±35), and its analog, [Ala 31,32,34,35 ]Ab(25±35), was studied. One nanosecond NPT molecular dynamics simulation was used to examine the structural stability of the peptides in water. Calculations were performed using the modi®ed GROMOS-87 force ®eld with SPC/E water model, applying the weak temperature and pressure coupling method. During the simulation of the Ab(25±35) structure, an initial helical structure was destroyed. In Ac-[Ala 31,32,34,35 ]Ab(25±35)-NHCH 3 , however, the helix was stable and even more so in the presence of Ca 21 , Mg 21 and Zn 21 cations. Between residues 27 and 34, mainly turn/bend and less frequently helix, respectively, characterized the secondary structure of Ab(25±35) and [Ala 31,32,34,35 ]Ab(25±35).
PLoS ONE, 2012
Amyloid b-protein (Ab) is central to the pathology of Alzheimer's disease. A 5% difference in the primary structure of the two predominant alloforms, Ab 1{40 and Ab 1{42 , results in distinct assembly pathways and toxicity properties. Discrete molecular dynamics (DMD) studies of Ab 1{40 and Ab 1{42 assembly resulted in alloform-specific oligomer size distributions consistent with experimental findings. Here, a large ensemble of DMD-derived Ab 1{40 and Ab 1{42 monomers and dimers was subjected to fully atomistic molecular dynamics (MD) simulations using the OPLS-AA force field combined with two water models, SPCE and TIP3P. The resulting all-atom conformations were slightly larger, less compact, had similar turn and lower b-strand propensities than those predicted by DMD. Fully atomistic Ab 1{40 and Ab 1{42 monomers populated qualitatively similar free energy landscapes. In contrast, the free energy landscape of Ab 1{42 dimers indicated a larger conformational variability in comparison to that of Ab 1{40 dimers. Ab 1{42 dimers were characterized by an increased flexibility in the N-terminal region D1-R5 and a larger solvent exposure of charged amino acids relative to Ab 1{40 dimers. Of the three positively charged amino acids, R5 was the most and K16 the least involved in salt bridge formation. This result was independent of the water model, alloform, and assembly state. Overall, salt bridge propensities increased upon dimer formation. An exception was the salt bridge propensity of K28, which decreased upon formation of Ab 1{42 dimers and was significantly lower than in Ab 1{40 dimers. The potential relevance of the three positively charged amino acids in mediating the Ab oligomer toxicity is discussed in the light of available experimental data. Citation: Barz B, Urbanc B (2012) Dimer Formation Enhances Structural Differences between Amyloid b-Protein (1-40) and (1-42): An Explicit-Solvent Molecular Dynamics Study. PLoS ONE 7(4): e34345.
Towards Understanding the Early Events in the Conformational Transition of Amyloid Beta Peptides
It is experimentally known that oligomerization of amyloid beta peptides is accompanied by a conformational transition from mainly alpha or random coil to beta sheets. The aim of this study is to analyze and compare the spatial orientation of hydration water near the peptide surface during this conformational transition of amyloid-beta 42 (Ab42) and amyloid-beta 40 (Ab40) peptides. Therefore, molecular dynamics (MD) simulations of 100 ns length with explicit representation of solvent were performed for individual amyloid beta monomers. Analysis was based on the radial distribution function (RDF) of hydration water for individual residues and for respective secondary structure elements. In all cases, initial results suggest that, in accord with the literature, the RDFs reveal the presence of two solvation shells around polar residues. Variations in RDF in the first solvation shell were found to be consistent with the physiochemical properties of the amino acids and were independent of the secondary structure element. However, individual residues that belonged to the secondary structure segments undergoing conformational transitions showed significant redistribution of water density. Further investigations, such as dimer formation and analysis of the orientation of water molecules near peptide surfaces are necessary to clarify the role played by surrounding water in the assembly of such unstructured peptides.
Dynamic properties of pH-dependent structural organization of the amyloidogenic β-protein (1-40)
Prion, 2009
The structural organization of the amyloidogenic β-protein containing 40 amino acid residues (Aβ40) was studied by the high temperature molecular dynamics simulations in the acidic (pH ~ 3) and basic (pH ~ 8) pH regions. The obtained data suggest that the central Ala21-Gly29 segment of Aβ40 can adopt folded and partially unfolded structures. At the basic pH, this segment forms folded structures stabilized by electrostatic interactions and hydrogen bonds. At the acidic pH, it forms partially unfolded structures. Two other segments flanking to the central segment exhibit the propensity to adopt unstable interconverting α-helical, 3 10-helical and turn-like structures. One of these segments is comprised of the Ala30-Val36 residues at both of the considered pHs. The second segment is comprised of the Glu11-Phe20 at the basic pH and of the Glu11-Val24 residues at the acidic pHs. The revealed pH-dependent structuration of the Aβ40 allowed us to suggest a possible scenario for initial Aβ aggregation. According to this scenario, the occurrence of the partially unfolded states of the Ala21-Gly29 segment plays main role in the Aβ oligomerization process.
Monomeric amyloid β-peptide (1-42) significantly populates compact fibril-like conformations
2020
The aggregation of the amyloid β (Aβ) peptide is a major hallmark of Alzheimer’s disease. This peptide can aggregate into oligomers, proto-fibrils, and mature fibrils, which eventually assemble into amyloid plaques. The peptide monomers are the smallest assembly units, and play an important role in most of the individual processes involved in amyloid fibril formation, such as primary and secondary nucleation and elongation. The structure of the Aβ monomer has been shown to be very dynamic and mostly disordered, both in experimental and in computational studies, similar to a random coil. This structural state of the monomer contrasts with the very stable and well defined structural core of the amyloid fibrils. An important question is whether the monomer can adopt transient fibril-like conformations in solution and what role such conformations might play in the aggregation process. Here we use enhanced and extensive molecular dynamics simulations to study the Aβ42 monomer structural ...
Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides
Biochemical and Biophysical Research Communications, 2007
Major constituents of the amyloid plaques found in the brain of Alzheimer's patients are the 39-43 residue b-amyloid (Ab) peptides. Extensive in vitro as well as in vivo biochemical studies have shown that the 40-and 42-residue Ab peptides play major roles in the neurodegenerative pathology of Alzheimer's disease. Although the two Ab peptides share common aggregation properties, the 42-residue peptide is more amyloidogenic and more strongly associated with amyloid pathology. Thus, characterizations of the two Ab peptides are of critical importance in understanding the molecular mechanism of Ab amyloid formation. In this report, we present combined CD and NMR studies of the monomeric states of the two peptides under both non-amyloidogenic (<5°C) and amyloid-forming conditions (>5°C) at physiological pH. Our CD studies of the Ab peptides showed that initially unfolded Ab peptides at low temperature (<5°C) gradually underwent conformational changes to more b-sheet-like monomeric intermediate states at stronger amyloidogenic conditions (higher temperatures). Detailed residue-specific information on the structural transition was obtained by using NMR spectroscopy. Residues in the N-terminal (3-12) and 20-22 regions underwent conformational changes to more extended structures at the stronger amyloidogenic conditions. Almost identical structural transitions of those residues were observed in the two Ab peptides, suggesting a similar amyloidogenic intermediate for the two peptides. The 42-residue Ab (1-42) peptide was, however, more significantly structured at the C-terminal region (39-42), which may lead to the different aggregation propensity of the two peptides.
Distinct Morphologies for Amyloid Beta Protein Monomer: Aβ 1–40 , Aβ 1–42 , and Aβ 1–40 (D23N)
Journal of Chemical Theory and Computation, 2011
Numerous experimental studies indicate that amyloid beta protein (Aβ) oligomers as small as dimers trigger Alzheimer's disease. Precise solution conformation of Aβ monomer is missing since it is highly dynamic and aggregation prone. Such a knowledge is however crucial to design drugs inhibiting oligomers and fibril formation. Here, we determine the equilibrium structures of the Aβ 1À40 , Aβ 1À42 , and Aβ 1À40 (D23N) monomers using an accurate coarse-grained force field coupled to Hamiltonian-temperature replica exchange molecular dynamics simulations. We observe that even if these three alloforms are mostly disordered at the monomeric level, in agreement with experiments and previous simulations on Aβ 1À40 and Aβ 1À42 , striking morphological differences exist. For instance, Aβ 1À42 and Aβ 1À40 (D23N) have higher β-strand propensities at the C-terminal, residues 30À42, than Aβ 1À40 . The D23N mutation enhances the conformational freedom of the residues 22À29 and the propensity for turns and β-strands in the other regions. It also changes the network of contacts; the N-terminal (residues 1À16) becoming more independent from the rest of the protein, leading to a less compact morphology than the wild-type sequence. These structural properties could explain in part why the kinetics and the final amyloid products vary so extensively between the Aβ 1À40 and the Aβ 1À40 (D23N) peptides.
Stability and Structure of Oligomers of the Alzheimer Peptide Aβ16–22: From the Dimer to the 32-Mer
Biophysical Journal, 2006
Several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are associated with amyloid fibrils formed by different polypeptides. We probe the structure and stability of oligomers of different sizes of the fragment Ab 16-22 of the Alzheimer b-amyloid peptide using atomic-detail molecular dynamics simulations with explicit solvent. We find that only large oligomers form a stable b-sheet aggregate, the minimum nucleus size being of the order of 8-16 peptides. This effect is attributed to better hydrophobic contacts and a better shielding of backbone-backbone hydrogen bonds from the solvent in bigger assemblies. Moreover, the observed stability of b-sheet aggregates with a different number of layers can be explained on the basis of their solvent-accessible surface area. Depending on the stacking interface between the sheets, we observe straight or twisted structures, which could be linked to the experimentally observed polymorphism of amyloid fibrils. To compare our 32-mer structure to experimental data, we calculate its x-ray diffraction pattern. Good agreement is found between experimentally and theoretically determined reflections, suggesting that our model indeed closely resembles the structures found in vitro.