Genipin and pyrogallol: Two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease

Kim, Sujin; Hyun, Da Gyeong; Nam, Yunkwon; Shin, Soo Jung; Im, Dongjoon; Kim, Hyeon soo; Leem, Seol Hwa; Park, Hyun Ha; Kim, Byeong-Hyeon; Park, Yong Ho; Cho, Eunbi; Goddard, William A.; Kim, Dong Hyun; Kim, Hugh I.; Moon, Minho

doi:10.1016/j.biopha.2023.115770

Cited by 5 publications

(1 citation statement)

References 64 publications

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“…The nucleation of Aβ42 and Aβ40 is modulated by various environmental factors, such as pH ( 78 ), metal ions ( 79 , 80 ), ionic strength, lipid membranes ( 81 ), small ligands ( 82 , 83 ), peptides ( 76 , 77 ), and proteins ( 84 , 85 ). Because of the similarity of the primary structure, binding partners of Aβ42 and Aβ40 interact with similar regions, regardless of the two additional residues.…”

Section: Structural Dynamics and Primary Nucleation Of Aβ42 And Aβ40 ...mentioning

confidence: 99%

Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

Im,

Choi

2024

BMB Rep

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Amyloid-β (Aβ) is one of the amyloidogenic intrinsically disordered proteins (IDPs) that self-assemble to protein aggregates, incurring cell malfunction and cytotoxicity. While Aβ has been known to regulate multiple physiological functions, such as enhancing synaptic functions, aiding in the recovery of the blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primary structure promotes pathological aggregations that are closely associated with the onset of Alzheimer's Disease (AD). Aβ proteins consist of multiple isoforms with 37-43 amino acid residues that are produced by the cleavage of amyloid-β precursor protein (APP). The hydrolytic products of APP are secreted to the extracellular regions of neuronal cells. Aβ 1-42 (Aβ42) and Aβ 1-40 (Aβ40) are dominant isoforms whose significance in AD pathogenesis has been highlighted in numerous studies to understand the molecular mechanism and develop AD diagnosis and therapeutic strategies. In this review, we focus on the differences between Aβ42 and Aβ40 in the molecular mechanism of amyloid aggregations mediated by the two additional residues (Ile41 and Ala42) of Aβ42. The current comprehension of Aβ42 and Aβ40 in AD progression is outlined, together with the structural features of Aβ42/Aβ40 amyloid fibrils, and the aggregation mechanisms of Aβ42/Aβ40. Furthermore, the impact of the heterogeneous distribution of Aβ isoforms during amyloid aggregations is discussed in the system mimicking the coexistence of Aβ42 and Aβ40 in human cerebrospinal fluid (CSF) and plasma. BMB Rep. www.bmbreports.org

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Section: Structural Dynamics and Primary Nucleation Of Aβ42 And Aβ40 ...mentioning

confidence: 99%

Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

Im,

Choi

2024

BMB Rep

Self Cite

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Activity of Streptomyces globosus OPF-9 against the important pathogen Alternaria longipes and biocontrol mechanisms revealed by multi-omic analyses

Wang,

Chen,

et al. 2024

Pesticide Biochemistry and Physiology

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Effects of All-Atom and Coarse-Grained Molecular Mechanics Force Fields on Amyloid Peptide Assembly: The Case of a Tau K18 Monomer

He,

Man,

Gao

et al. 2024

J. Chem. Inf. Model.

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To propose new mechanism-based therapeutics for Alzheimer's disease (AD), it is crucial to study the kinetics and oligomerization/aggregation mechanisms of the hallmark tau proteins, which have various isoforms and are intrinsically disordered. In this study, multiple all-atom (AA) and coarse-grained (CG) force fields (FFs) have been benchmarked on molecular dynamics (MD) simulations of K18 tau (M243−E372), which is a truncated form (130 residues) of full-length tau (441 residues). FF19SB is first excluded because the dynamics are too slow, and the conformations are too stable. All other benchmarked AAFFs (Charmm36m, FF14SB, Gromos54A7, and OPLS-AA) and CGFFs (Martini3 and Sirah2.0) exhibit a trend of shrinking K18 tau into compact structures with the radius of gyration (ROG) around 2.0 nm, which is much smaller than the experimental value of 3.8 nm, within 200 ns of AA-MD or 2000 ns of CG-MD. Gromos54A7, OPLS-AA, and Martini3 shrink much faster than the other FFs. To perform meaningful postanalysis of various properties, we propose a strategy of selecting snapshots with 2.5 < ROG < 4.5 nm, instead of using all sampled snapshots. The calculated chemical shifts of all C, CA, and CB atoms have very good and close rootmean-square error (RMSE) values, while Charmm36m and Sirah2.0 exhibit better chemical shifts of N than other FFs. Comparing the calculated distributions of the distance between the CA atoms of CYS291 and CYS322 with the results of the FRET experiment demonstrates that Charmm36m is a perfect match with the experiment while other FFs exhibit limitations. In summary, Charmm36m is recommended as the best AAFF, and Sirah2.0 is recommended as an excellent CGFF for simulating tau K18.

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Genipin and pyrogallol: Two natural small molecules targeting the modulation of disordered proteins in Alzheimer's disease

Cited by 5 publications

References 64 publications

Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

Distinctive contribution of two additional residues in protein aggregation of Aβ42 and Aβ40 isoforms

Activity of Streptomyces globosus OPF-9 against the important pathogen Alternaria longipes and biocontrol mechanisms revealed by multi-omic analyses

Effects of All-Atom and Coarse-Grained Molecular Mechanics Force Fields on Amyloid Peptide Assembly: The Case of a Tau K18 Monomer

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