Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Nasica‐Labouze, Jessica; Nguyen, Phuong H.; Sterpone, Fabio; Berthoumieu, Olivia; Buchete, Nicolae‐Viorel; Côté, Sébastien; Simone, Alfonso De; Doig, Andrew J.; Faller, Peter; Garcı́a, Angel E.; Laio, Alessandro; Li, Mai Suan; Melchionna, Simone; Mousseau, Normand; Mu, Yuguang; Paravastu, Anant K.; Pasquali, Samuela; Rosenman, David J.; Strodel, Birgit; Tarus, Bogdan; Viles, John H.; Zhang, Tong; Wang, Chunyu; Derreumaux, Philippe

doi:10.1021/cr500638n

Cited by 552 publications

(652 citation statements)

References 555 publications

(1,443 reference statements)

Supporting

Mentioning

611

Contrasting

Unclassified

Order By: Relevance

“…The study of the secondary structure of Aβ species using Fourier transform infrared spectroscopy suggests that fibrillar forms of Aβ are organized in a parallel β-sheet conformation, much like in the complete fibril structure constructed from solid-state NMR data by Petkova et al (4), whereas the prefibrillar oligomers contain mainly antiparallel β-sheets (5). Numerous computer simulation studies of both the monomer and higher aggregates using models ranging in complexity from fully atomistic simulations in solvent to lattice models have been undertaken to fill the knowledge gap (6)(7)(8). It remains, however, unclear what the exact tertiary arrangements of the β-sheets in the Aβ prefibrillar oligomers are as well as how the structures and stabilities of the oligomers change as they grow.…”

mentioning

confidence: 99%

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

Zheng

Tsai

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

129

193

View full text Add to dashboard Cite

A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer's disease.misfolding | amyloid funnel | nucleation A lzheimer's disease is associated with the deposition of amyloid-β (Aβ) protein aggregates in the brain (1). Soluble Aβ oligomers, intermediates formed early in the aggregation process, can cause synaptic dysfunction, whereas the later-formed insoluble fibrils may function as reservoirs of the toxic oligomers (2). Owing to their stoichiometric complexity and transience, the early oligomeric forms are difficult to study in the laboratory. Nevertheless, distinct forms of oligomers, described as prefibrillar and fibrillar, have been found to bind differently to conformation-dependent antibodies (3): the fibrillar oligomers and mature fibrils both display a common epitope that is absent from the prefibrillar oligomers. The study of the secondary structure of Aβ species using Fourier transform infrared spectroscopy suggests that fibrillar forms of Aβ are organized in a parallel β-sheet conformation, much like in the complete fibril structure constructed from solid-state NMR data by Petkova et al. (4), whereas the prefibrillar oligomers contain mainly antiparallel β-sheets (5). Numerous computer simulation studies of both the monomer and higher aggregates using models ranging in complexity from fully atomistic simulations in solvent to lattice models have been undertaken to fill the knowledge gap (6-8). It remains, however, unclear what the exact tertiary arrangements of the β-sheets in the Aβ prefibrillar oligome...

show abstract

mentioning

confidence: 99%

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

Zheng

Tsai

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

129

193

View full text Add to dashboard Cite

show abstract

“…The central part of this hairpin structure consists of a hydrophilic region flanked by hydrophobic ␤-sheet-forming segments at both ends (5)(6)(7)(8)(9)(10). This particular shape is believed to be dictated by the specific pattern of hydrophobic and charged residues in the A␤ sequence and has been identified even in soluble A␤ aggregates (7,(11)(12)(13)(14)(15)(16)(17), including the very early stage oligomers of A␤ (18). Chemically constraining the side chains of Asp 23 and Lys 28 accelerates the kinetics of A␤ aggregation by stabilizing the hairpin structure (5).…”

mentioning

confidence: 99%

Steric Crowding of the Turn Region Alters the Tertiary Fold of Amyloid-β18–35 and Makes It Soluble

Chandrakesan

Bhowmik

Sarkar

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

A␤ self-assembles into parallel cross-␤ fibrillar aggregates, which is associated with Alzheimer's disease pathology. A central hairpin turn around residues 23-29 is a defining characteristic of A␤ in its aggregated state. Major biophysical properties of A␤, including this turn, remain unaltered in the central fragment A␤ 18 -35 . Here, we synthesize a single deletion mutant, ⌬G25, with the aim of sterically hindering the hairpin turn in A␤ 18 -35 . We find that the solubility of the peptide goes up by more than 20-fold. Although some oligomeric structures do form, solution state NMR spectroscopy shows that they have mostly random coil conformations. Fibrils ultimately form at a much higher concentration but have widths approximately twice that of A␤ 18 -35 , suggesting an opening of the hairpin bend. Surprisingly, two-dimensional solid state NMR shows that the contact between Phe 19 and Leu 34 residues, observed in full-length A␤ and A␤ 18 -35 , is still intact in these fibrils. This is possible if the monomers in the fibril are arranged in an antiparallel ␤-sheet conformation. Indeed, IR measurements, supported by tyrosine cross-linking experiments, provide a characteristic signature of the antiparallel ␤-sheet. We conclude that the self-assembly of A␤ is critically dependent on the hairpin turn and on the contact between the Phe 19 and Leu 34 regions, making them potentially sensitive targets for Alzheimer's therapeutics. Our results show the importance of specific conformations in an aggregation process thought to be primarily driven by nonspecific hydrophobic interactions.Alzheimer's disease pathology has been associated with the aggregation of amyloid ␤ (A␤), 6 a 39 -43-amino acid-long peptide (1, 2). In this process, the unstructured monomers of A␤ get converted into amyloid fibrils composed of hairpin-shaped monomeric units assembled in a parallel ␤ sheet arrangement (3, 4). The central part of this hairpin structure consists of a hydrophilic region flanked by hydrophobic ␤-sheet-forming segments at both ends (5-10). This particular shape is believed to be dictated by the specific pattern of hydrophobic and charged residues in the A␤ sequence and has been identified even in soluble A␤ aggregates (7,(11)(12)(13)(14)(15)(16)(17), including the very early stage oligomers of A␤ (18 , and stabilizes the soluble monomeric and oligomeric assemblies of A␤ (19). This hairpin turn thus seems to be a critical factor dictating the self-assembly of A␤ under physiological conditions. Studying the influence of the turn region on the properties of A␤, separately from that of the distal terminal regions and without changing the electrostatics, can yield valuable information on the logic of A␤ assembly.A␤ aggregation appears to be primarily hydrophobic in nature. In fact a contact between hydrophobic regions containing Phe 19 and Leu 34 is one of the earliest contacts formed during the aggregation of amyloid ␤ (18). In a generic hydrophobic aggregate, the burial of the hydrophobic surface can in principle proceed in an ...

show abstract

“…Molecular dynamics simulations were applied to analyse the dynamics behavior of the ligand, and obtain more detailed ligand-protein interaction information. [25][26][27][28] The stepwise description of the molecular modeling was shown in Fig. S1 (see ESI †).…”

Section: -21mentioning

confidence: 99%

Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors

2017

View full text Add to dashboard Cite

The forced expression of phosphoinositide 3-kinase d (PI3Kd) in B cells was found to be oncogenic, rendering PI3Kd an attractive drug target for chronic lymphocytic leukaemia. This study aimed to systemically explore the interaction mechanism of novel quinazolinone scaffold-based derivatives as PI3Kd inhibitors using 3D-QSAR, molecular docking, pharmacophore model and molecular dynamics (MD) simulations. The 3D-QSAR models CoMFA, CoMSIA and Topomer CoMFA were established to discover critical structural factors affecting PI3Kd inhibitory activity. The models showed suitable reliabilities (q 2 0.741, 0.712 and 0.711) and predictive abilities (r pred 2 0.851, 0.738 and 0.828, respectively).Contour maps indicated that the bioactivity of PI3Kd inhibitor was affected most by electrostatic and hydrophobic fields. The Surflex-Dock and pharmacophore model result showed that enhancing the Hbond interaction of the key substituents around the 2-and 4-positions of pyrimidine with Glu826, Val828 and Asp911, as well as the electrostatic interactions of substituents around the 3-position of benzene with Ser831, Asp832 and Asn836, significantly affected the improvement in the activity and stability of the inhibitor. Based on these results, 10 novel PI3Kd inhibitors with higher predicted activity and binding affinity were designed by introducing the heterocycles pyrrolopyridine or purine. 10 ns MD simulations further study the stable docking conformation of designed compounds, which showed strong hydrogen bond interactions with key residues Ser831 and Asp832 in a propeller-like fashion.These results provided strong guidance for the discovery and optimization of novel potent PI3Kd selective inhibitors.

show abstract

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Abstract: Graphical abstract

Cited by 552 publications

References 555 publications

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)

Steric Crowding of the Turn Region Alters the Tertiary Fold of Amyloid-β18–35 and Makes It Soluble

Molecular modeling studies of quinazolinone derivatives as novel PI3Kδ selective inhibitors

Contact Info

Product

Resources

About