Identifying the key residues instrumental in imparting stability to amyloid beta protofibrils – a comparative study using MD simulations of 17–42 residues

Probing the fibrillation of lysozyme by nanoscale-infrared spectroscopy

“…Surprisingly, the formation of fibrils does not depend on the amino acid sequence, overall structure, and function of the protein and consists of a core structure mainly containing cross-b-fiber . Although, the understanding of diseased proteins such as amyloid peptides (Ab) (Dutta & Basu, 2020;Grasso, Leanza, Morbiducci, Danani, & Deriu, 2019;Shuaib, Saini, Goyal, & Goyal, 2020;Turner, Mutter, & Platts, 2019) and their inhibition (Ghorbani, Soleymani, Allahverdi, Shojaeilangari, & Naderi-Manesh, 2019;Liu, Ma, Sang, & Lu, 2019;Narang, Goyal, & Goyal, 2019) is documented, there is still a need to explore the fibrillation process for better therapeutics.…”

Destabilization potential of beta sheet breaker peptides on Abeta fibril structure: an insight from molecular dynamics simulation study

“…The major factors that were considered by most of the researchers for evaluating the destabilization potential of the ligands are secondary structure content especially beta and coil content, salt bridge distance between Asp23-Lys28 (especially in U-shaped model), inter-chain hydrogen and hydrophobic interaction. 64,65,[81][82][83][84][85][86][87] In the current work, it was observed that binding of peptides with Abeta protobril has resulted in the loss of beta structure and gain of coil structure. This is in accordance with previous studies showing increase of coil and decrease of beta structures.…”

“…Along with Phe 20 and Phe 19, Glu 22 was also seen to have contribution in free energy of binding. Dutta et al 84 also showed the importance of Glu 22 residue in maintaining the D23-K28 salt bridge.…”

“…structure. 83,84 The salt bridge between Cg of Asp23 and Nx of Lys28 plays an important role in the stabilization of cross beta structure between chains of Abeta oligomer. 83 As the peptides tend to bind to either chain A or chain E of the protobril, the interchain salt bridge between chain A and chain B, and between chain D and chain E was calculated.…”

Molecular mechanisms of amyloid disaggregation

“…Using SMD, the authors discovered that most of the peptides disassociated from the protofibril when the interpeptide backbone hydrogen bonding between Gly33 and Met 25 was broken [123] . Similar computational methods were used by Dutta et al on the solution NMR structure of Aβ protofibril L17-A42 (PDB ID: 2BEG) and hypothesized that the aromatic residues and hydrophobic residues within the beta-strands of fibrils were also critical for packing the amyloid core and thus provide stability of the fibrils [124] . SMD involves the determination of the breaking threshold of peptide disassociation from the protofibrils or in other words, the important interaction required for fibril stability by pulling a peptide away from the protofibrils as a function of time.…”