The stability of cylindrin β‐barrel amyloid oligomer models—A molecular dynamics study

Berhanu, Workalemahu M.; Hansmann, Ulrich H. E.

doi:10.1002/prot.24302

Cited by 43 publications

(39 citation statements)

References 44 publications

(98 reference statements)

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“…We estimate the pore diameter by measuring the distance between the central M 35 residues of the adjacent U-shaped sub-units and averaging these values. 29 The observed pore diameter range of 19.5-20 Å for the 6-and 12-layer Ab oligomers (Table I) is comparable to the average pore diameter of 15-20 Å that was observed in experiments of amyloids formed by E22G Ab . 17 The resulting interior channels are water-accessible.…”

Section: Alred Et Alsupporting

confidence: 78%

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

Alred

Phillips²,

Berhanu³

et al. 2015

Protein Science

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The amyloid beta (Ab) oligomers and fibrils that are found in neural tissues of patients suffering from Alzheimer's disease may either cause or contribute to the pathology of the disease. In vitro, these Ab-aggregates are characterized by structural polymorphism. However, recent solid state NMR data of fibrils acquired post mortem from the brains of two Alzheimer's patients indicate presence of only a single, patient-specific structure. Using enhanced molecular dynamic simulations we investigate the factors that modulate the stability of Ab-fibrils. We find characteristic differences in molecular flexibility, dynamics of interactions, and structural behavior between the brain-derived Ab-fibril structure and in vitro models. These differences may help to explain the lack of polymorphism in fibrils collected from patient brains, and have to be taken into account when designing aggregation inhibitors and imaging agents for Alzheimer's disease.

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Section: Alred Et Alsupporting

confidence: 78%

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

Alred

Phillips²,

Berhanu³

et al. 2015

Protein Science

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“…This sequence was tested by Eisenberg and coworkers [24] and found to form a beta-barrel structure. All other sequences that may potentially form cylindrin-like structures and have been studied using molecular dynamics [26] are also given in Table 1. Hence, Table 1 includes cylindrin (K11V), cylindrin mutants (K11V V2L , K11V V4AV8A , K11V V4GV8G , K11V V4LV8L ), as well as tandem-repeat cylindrin (K11V-TR) and its mutant (K11V V4W -TR).…”

Section: Sequencesmentioning

confidence: 99%

“…The structures of K11V and K11V-TR were derived experimentally by Laganowsky and colleagues (PDB codes: 3SGO and 3SGR, respectively) [24]. These structures, Table 1 Cylindrin (K11V), tandem repeat cylindrin (K11V-TR), and mutant sequences [24,26]. Positions given in bold are mutated amino acids (for the cylindrin mutants) or added amino acids (for the tandemrepeat cylindrin)…”

Section: Sequencesmentioning

confidence: 99%

Comparative modeling of hypothetical amyloid pores based on cylindrin

Zulpo

Kotulska

2015

J Mol Model

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Cylindrin is a six-stranded antiparallel beta barrel obtained from amyloidogenic strands of crystallin. It induces cell toxicity through an unknown mechanism. In this work, the potential use of the structure of cylindrin as a template for modeling amyloid pores-hypothetical transmembrane structures which appear during amyloid diseases-was studied. Using comparative modeling (performed by Modeller), we tested the stability of cylindrin-based pores made from several amyloid-forming and non-amyloid-forming strands deriving from mutated cylindrin and the prion sup35. We showed that cylindrin could be used as a template for modeling pores made from strands of amyloid proteins, but that the cylindrin structure does not result from the amyloidogenicity of these fragments, as fibril non-formers from the prion were also able to form a similar structure. Finally, we tested whether the cellular toxicity of cylindrin and related structures could be due to its incorporation into the cell membrane, leading to the creation of conducting ionic channels. The results of modeling indicate that cylindrin and tandem-repeat cylindrin, mutants of them, and cylindrin-like amyloid pores from prion sequences can only localize on the periphery of the membrane, and are not able to conduct any ions into the cell. These findings explain experimental results obtained for large unilamellar vesicles incubated with cylindrin, where conductance was not observed.

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“…The selected snapshots serve as a start point for three independent trajectories (with different velocity distributions) of 50 ns length that relies on the Amber12 software and the ff99SB 37 forcefield. 26,53 Approximations of the DG values are calculated from the last 10 ns of these trajectories and exclude contributions from the conformational entropy. This is an often used approximation in amyloid studies 29,30 and partially motivated by the difficulties in estimating the conformational entropy from a normal mode analysis using a rigid-rotor harmonic-oscillator ideal-gas approximation of the system that leads to large systematic and statistical errors.…”

Section: Computational Setupmentioning

confidence: 99%

Effect of single point mutations in a form of systemic amyloidosis

Bhavaraju

Hansmann

2015

Protein Science

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Amyloid deposits of light-chain proteins are associated with the most common form of systemic amyloidosis. We have studied the effects of single point mutations on amyloid formation of these proteins using explicit solvent model molecular dynamics simulations. For this purpose, we compare the stability of the wild-type immunoglobulin light-chain protein REI in its native and amyloid forms with that of four mutants: R61N, G68D, D82I, and A84T. We argue that the experimentally observed differences in the propensity for amyloid formation result from two effects. First, the mutant dimers have a lower stability than the wild-type dimer due to increase exposure of certain hydrophobic residues. The second effect is a shift in equilibrium between monomers with amyloid-like structure and such with native structures. Hence, when developing drugs against light-chain associated systemic amyloidosis, one should look for components that either stabilize the dimer by binding to the dimer interface or reduce for the monomers the probability of the amyloid form.

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The stability of cylindrin β‐barrel amyloid oligomer models—A molecular dynamics study

Cited by 43 publications

References 44 publications

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

Comparative modeling of hypothetical amyloid pores based on cylindrin

Effect of single point mutations in a form of systemic amyloidosis

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