Inhibitory mechanism of lithospermic acid on fibrillation of type 2 diabetes associated islet amyloid polypeptide

Journal of Molecular Graphics and Modelling, Journal Year: 2025, Volume and Issue: 136, P. 108972 - 108972

Published: Jan. 30, 2025

Language: Английский

---

Deciphering the Inhibitory Mechanism of ALS-Associated N352S and S352p Variants against TDP-43 Aggregation and Its Destabilization Effect on TDP-43 Protofibrils

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Amyotrophic lateral sclerosis (ALS) is closely related to ubiquitin-positive inclusions formed by transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43). Previous experiments identified that the ALS-linked familial variant, N352S (asparagine substituted serine), and subsequent phosphorylation S352 (S352p) are associated with aggregation TDP-43. However, underlying molecular mechanisms still not fully understood. By performing all-atom explicit-solvent replica exchange dynamics (REMD) simulations a total simulation time 100.8 μs, we scrutinized impact mutation its variant S352p on conformational ensembles TDP-43342-366 dimer. Our results show both variants could promote formation unstructured conformation impede β-structure helix content, inhibitive effect S352P more obvious. Further analyses suggest H-bonding hydrophobic interaction among peptides, as well R361-E362 salt bridge, attenuated variants. Additional MD reduce structural stability region lower number H-bonds contacts two clusters, thus possessing destabilization TDP-43282-360 protofibrils. unmask mechanism toward inhibition prove protofibril-destabilizing effects these variants, which may be helpful for designing drugs treatment ALS.

Language: Английский

---

Deciphering the impact of F23L mutation on the aggregation propensity of human islet amyloid polypeptide using molecular simulations

Journal of Molecular Liquids, Journal Year: 2024, Volume and Issue: 411, P. 125775 - 125775

Published: Aug. 22, 2024

Language: Английский

---

Unveiling molecular mechanism underlying inhibition of human islet amyloid polypeptide fibrillation by benzene carboxylic acid-peptide conjugate

Journal of Molecular Liquids, Journal Year: 2024, Volume and Issue: 416, P. 126426 - 126426

Published: Nov. 7, 2024

Language: Английский

---