Molecular Dynamics Simulation of Amyloid β Dimer Formation

Urbanc, Brigita; Cruz, Luis; Ding, Feng; Sammond, Deanne W.; Khare, Sagar D.; Buldyrev, Sergey V.; Stanley, H. Eugene; Dokholyan, Nikolay V.

doi:10.1529/biophysj.104.040980

Cited by 200 publications

(271 citation statements)

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“…33). The DMD simulation method has been adapted successfully to model proteins (23,25,26,30) and used to study folding and aggregation of a three-helix-bundle protein (22,24), the SH3 protein (27)(28)(29), and A␤ (31,32).…”

Section: Methodsmentioning

confidence: 99%

“…In vivo and in vitro studies suggest that the time regime of A␤ oligomerization is measured in seconds to weeks (15,21), at least 7 orders of magnitude greater than that accessible by all-atom MD. To overcome this temporal barrier and enable the study of A␤ folding and assembly, we combined an efficient discrete MD (DMD) algorithm with a coarse-grained protein model (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). This simulation approach produces oligomerization speeds Ϸ10 10 greater than those obtainable with traditional MD.…”

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confidence: 99%

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In silico study of amyloid β-protein folding and oligomerization

Urbanc

Cruz

Yun

et al. 2004

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

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327

478

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Experimental findings suggest that oligomeric forms of the amyloid ␤ protein (A␤) play a critical role in Alzheimer's disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, A␤40 and A␤42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. A␤40 forms significantly more dimers than A␤42, whereas pentamers are significantly more abundant in A␤42 relative to A␤40. Structure analysis reveals a turn centered at Gly-37-Gly-38 that is present in a folded A␤42 monomer but not in a folded A␤40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in A␤42 pentamer formation. A␤ pentamers have a globular structure comprising hydrophobic residues within the pentamer's core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of A␤40 pentamers are more spatially restricted than A␤42 pentamers. A␤40 pentamers form a ␤-strand structure involving Ala-2-Phe-4, which is absent in A␤42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the A␤42 pentamer being more exposed and thus more prone to form larger oligomers.Alzheimer's disease ͉ discrete molecular dynamics ͉ four-bead protein model ͉ oligomer formation T he amyloid ␤-protein (A␤) has been strongly linked to the etiology and pathogenesis of Alzheimer's disease (AD). A␤ assembles into amyloid fibrils and smaller, oligomeric assemblies. Experimental and clinical findings suggest that protofibrillar intermediates (1-3) and oligomeric forms (4-13) of A␤ may be particularly important. If so, elucidating the structures of these A␤ oligomers and the mechanisms of their formation is critical for developing therapeutic agents. Unlike proteins with stable folds, A␤ oligomers are metastable. They cannot be crystallized for x-ray diffraction studies nor can they be easily studied by using solutionphase NMR. Monomers and oligomers are also in dynamic equilibrium, which makes the study of pure populations of conformers using classical biophysical techniques difficult.A␤ exists in two predominant forms, 40 (A␤40) or 42 (A␤42) amino acids in length. Of the two, A␤42 is associated most strongly with an increased risk for AD, is more neurotoxic, and forms fibrils significantly faster. Recent experiments demonstrated that A␤ oligomers can be covalently cross-linked, and therefore stabilized, by using the technique of photo-induced cross-linking of unmodified proteins (PICUP) (14). During PICUP coupled with si...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

In silico study of amyloid β-protein folding and oligomerization

Urbanc

Cruz

Yun

et al. 2004

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

Self Cite

327

478

View full text Add to dashboard Cite

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“…12 Over the past several years, a wide range of theoretical techniques have also been deployed to understand the formation of soluble oligomers as well. 13 For example, Klimov and Thirumalai studied a heptapeptide sequence A␤ [16][17][18][19][20][21][22] and found oligomers composed of antiparallel beta sheets. 14 Hwang et al used a thousand dimerization simulations of the same peptide with a continuum solvent model and found that kinetics played an important role in the structure formation.…”

Section: Introductionmentioning

confidence: 99%

“…15 In apparent contrast, Urbanc et al found that dimers of beta sheet structures were not stable conformations for the whole length peptides A␤ 40 and A␤ 42 . 16 More recently, using a combination of simplified protein models and discrete molecular dynamics ͑MD͒, Urbanc et al predicted globular oligomers with a hydrophobic core and exposed N-terminal residues, besides identifying residues that are involved in the oligomer formation. 17 In a recent work, Dagmar et al used fully atomistic simulations of the monomer and observed that A␤ samples many ␤-rich conformations which might serve as precursors to oligomerization.…”

Section: Introductionmentioning

confidence: 99%

Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach

Kelley

Vishal

Krafft

et al. 2008

The Journal of Chemical Physics

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Here, we present a novel computational approach for describing the formation of oligomeric assemblies at experimental concentrations and timescales. We propose an extension to the Markovian state model approach, where one includes low concentration oligomeric states analytically. This allows simulation on long timescales ͑seconds timescale͒ and at arbitrarily low concentrations ͑e.g., the micromolar concentrations found in experiments͒, while still using an all-atom model for protein and solvent. As a proof of concept, we apply this methodology to the oligomerization of an A␤ peptide fragment ͑A␤ 21-43 ͒. A␤ oligomers are now widely recognized as the primary neurotoxic structures leading to Alzheimer's disease. Our computational methods predict that A␤ trimers form at micromolar concentrations in 10 ms, while tetramers form 1000 times more slowly. Moreover, the simulation results predict specific intermonomer contacts present in the oligomer ensemble as well as putative structures for small molecular weight oligomers. Based on our simulations and statistical models, we propose a novel mutation to stabilize the trimeric form of A␤ in an experimentally verifiable manner.

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“…We describe the use of simplified protein models in conjunction with the rapid simulations methodology, discrete molecular dynamics (DMD). Despite the use of DMD in simulating polymer fluids [6,7], single homopolymers [7,8], proteins [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25], protein aggregates [13,17,23,24,26], and gases and liquids [27,28], we believe it is significantly underutilized in the molecular-modeling field.…”

Section: Introductionmentioning

confidence: 99%