Alanine Scanning Effects on the Biochemical and Biophysical Properties of Intrinsically Disordered Proteins: A Case Study of the Histidine to Alanine Mutations in Amyloid-β<sub>42</sub>

Coskuner‐Weber, Orkid; Uversky, Vladimir N.

doi:10.1021/acs.jcim.8b00926

Cited by 16 publications

(15 citation statements)

References 94 publications

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“…To gain more insights, Alies et al conducted recently XANES and NMR measurements of Zn(II) binding to several modified species . We should mention here that mutations affect the biochemical and biophysical characteristics of Aβ . XANES measurements supported a four-coordinated metal center, thus (i) supporting the conclusions from the EXAFS data for the same Zn:Aβ species and (ii) revealing that a mutated residue that is no longer able to bind to the Zn(II) ion is replaced by another residue ligand, keeping the coordination number at four in the Zn(II):Aβ complexes .…”

Section: Metal Ions and Aβ: Insights From Experimentssupporting

confidence: 77%

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Strodel

Coskuner‐Weber

2019

J. Chem. Inf. Model.

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Monomers and oligomers of the amyloid-β peptide aggregate to form the fibrils found in the brains of Alzheimer’s disease patients. These monomers and oligomers are largely disordered and can interact with transition metal ions, affecting the mechanism and kinetics of amyloid-β aggregation. Due to the disordered nature of amyloid-β, its rapid aggregation, as well as solvent and paramagnetic effects, experimental studies face challenges in the characterization of transition metal ions bound to amyloid-β monomers and oligomers. The details of the coordination chemistry between transition metals and amyloid-β obtained from experiments remain debated. Furthermore, the impact of transition metal ion binding on the monomeric or oligomeric amyloid-β structures and dynamics are still poorly understood. Computational chemistry studies can serve as an important complement to experimental studies and can provide additional knowledge on the binding between amyloid-β and transition metal ions. Many research groups conducted first-principles calculations, ab initio molecular dynamics simulations, quantum mechanics/classical mechanics simulations, and classical molecular dynamics simulations for studying the interplay between transition metal ions and amyloid-β monomers and oligomers. This review summarizes the current understanding of transition metal interactions with amyloid-β obtained from computational chemistry studies. We also emphasize the current view of the coordination chemistry between transition metal ions and amyloid-β. This information represents an important foundation for future metal ion chelator and drug design studies aiming to combat Alzheimer’s disease.

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Section: Metal Ions and Aβ: Insights From Experimentssupporting

confidence: 77%

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Strodel

Coskuner‐Weber

2019

J. Chem. Inf. Model.

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“…Following our previous studies, the particle mesh Ewald method was utilized for capturing long‐range interactions. The bonds to hydrogen atoms were constrained using the SHAKE algorithm (Coskuner‐Weber & Uversky, 2019).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies showed that Aβ undergoes a conformational change from random coil to α‐helices and β‐sheets during the fibril assembly process (Ow & Dunstan, 2014). The initial conformational changes of the Aβ monomer during its assembly include formation of turns, α‐helices, and β‐strands (Coskuner & Uversky, 2017; Coskuner & Wise‐Scira, 2013; Coskuner‐Weber & Uversky, 2019). Some of these elements are transitory and others are perpetuated through the fibril assembly process.8 Identifying and blocking α‐helices and β‐sheets could aid in the design of new therapeutics (Uversky, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…However, as aforementioned, experiments face challenges in the accurate identification of epitope regions of Aβ. Therefore, molecular dynamics (MD) simulation experiments with or without special sampling techniques were used for identifying residues that can adopt α‐helices and β‐sheets (Coskuner & Uversky, 2017; Coskuner & Wise‐Scira, 2013; Coskuner‐Weber & Uversky, 2019). Few groups studied the impact of the chosen force field parameters on the epitope region identification of Aβ (Lincoff et al., 2019; Weber & Uversky, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Secondary structure dependence of amyloid‐β(1–40) on simulation techniques and force field parameters

et al. 2021

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Our recent studies revealed that none of the selected widely used force field parameters and molecular dynamics simulation techniques yield structural properties for the intrinsically disordered α‐synuclein that are in agreement with various experiments via testing different force field parameters. Here, we extend our studies on the secondary structure properties of the disordered amyloid‐β(1–40) peptide in aqueous solution. For these purposes, we conducted extensive replica exchange molecular dynamics simulations and obtained extensive molecular dynamics simulation trajectories from David E. Shaw group. Specifically, these molecular dynamics simulations were conducted using various force field parameters and obtained results are compared to our replica exchange molecular dynamics simulations and experiments. In this study, we calculated the secondary structure abundances and radius of gyration values for amyloid‐β(1–40) that were simulated using varying force field parameter sets and different simulation techniques. In addition, the intrinsic disorder propensity, as well as sequence‐based secondary structure predisposition of amyloid‐β(1–40) and compared the findings with the results obtained from molecular simulations using various force field parameters and different simulation techniques. Our studies clearly show that the epitope region identification of amyloid‐β(1–40) depends on the chosen simulation technique and chosen force field parameters. Based on comparison with experiments, we find that best computational results in agreement with experiments are obtained using the a99sb*‐ildn, charmm36m, and a99sb‐disp parameters for the amyloid‐β(1–40) peptide in molecular dynamics simulations without parallel tempering or via replica exchange molecular dynamics simulations.

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“…Despite differences in conservation, of the 8 amino acids that account for 75% of the total composition, LCRs share five highly used amino acids with epitopes (Asn, Glu, Gly, Lys, Ser) while another three are preferentially used only in LCRs (Ala, Pro, Thr). The preference for these last three amino acids is not surprising considering all three are found in high frequency in disordered proteins (see below; Theillet et al 2013;Coskuner-Weber & Uversky 2019;Perez et al 2014).…”

Section: Low Complexity Sequences As Epitope-like Regionsmentioning

confidence: 99%

Genomic evolution of epitopes and Low Complexity Regions in Plasmodium

Medley

Beaudet

Piontkivska

et al. 2021

Preprint

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Despite decades-long efforts to eradicate malaria, pathogens genomic complexity and variability continue to pose major challenges for the vaccine and drug development. Here we examined the evolutionary history of epitopes and epitope-like regions to determine whether they share underlying evolutionary mechanisms and potential functions that are relevant to pathogens interactions with the host immune response. Our comparative sequence analyses contrasted patterns of sequence conservation, amino acid composition, and protein structure of epitopes and low complexity regions (LCRs) in 21 Plasmodium species. Our results revealed many similarities in amino acid composition and preferred secondary structures between epitopes and LCRs; however, we also identified differences in evolutionary trends where LCRs exhibit overall lower sequence conservation and higher disorder. We also found that both epitopes and LCRs have a wide array of configurations, with various levels of sequence conservation and structural order. We propose that such combination of different levels of conservation and structural order between epitopes and LCRs in the same gene play a role in maintaining the functional integrity required by the pathogen along with the variability necessary to evade the host immune response, with LCRs playing a role in the evasion particularly in the vicinity of conserved epitopes. Overall, our results suggest that there are at least two categories of LCRs, where some LCRs play a potential protective role for conserved (ordered) epitopes because of their variable (or disordered) sequence, while others are less disordered and are as conserved as epitopes. The former ones may be an evolutionary necessity for Plasmodium to maintain the diversity of epitopes, while the latter category may serve currently unknown function(s) and deserve to be examined in greater detail. Our findings show that there may be many more candidate targets for future anti-malarial treatments than initially thought and that some of these targets may work across strains and species.

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Alanine Scanning Effects on the Biochemical and Biophysical Properties of Intrinsically Disordered Proteins: A Case Study of the Histidine to Alanine Mutations in Amyloid-β₄₂

Cited by 16 publications

References 94 publications

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Secondary structure dependence of amyloid‐β(1–40) on simulation techniques and force field parameters

Genomic evolution of epitopes and Low Complexity Regions in Plasmodium

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Alanine Scanning Effects on the Biochemical and Biophysical Properties of Intrinsically Disordered Proteins: A Case Study of the Histidine to Alanine Mutations in Amyloid-β42

Cited by 16 publications

References 94 publications

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Transition Metal Ion Interactions with Disordered Amyloid-β Peptides in the Pathogenesis of Alzheimer’s Disease: Insights from Computational Chemistry Studies

Secondary structure dependence of amyloid‐β(1–40) on simulation techniques and force field parameters

Genomic evolution of epitopes and Low Complexity Regions in Plasmodium

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Alanine Scanning Effects on the Biochemical and Biophysical Properties of Intrinsically Disordered Proteins: A Case Study of the Histidine to Alanine Mutations in Amyloid-β₄₂