Molecular Insights into Destabilization of Alzheimer’s Aβ Protofibril by Arginine Containing Short Peptides: A Molecular Modeling Approach

Abstract

Aggregation of amyloid beta (Aβ) peptides leads to formation of fibrilar, soluble oligomers, and their deposition is a key event in progression of Alzheimer’s disease (AD). Recent experimental studies of Arg-Arg-7-amino-4-trifluoromethylcoumarin (RR-AFC) showed significant Aβ aggregation inhibition, but its molecular mechanism is not yet clear. Hence, the present study aims at exploring the underlying mechanism of destabilization and inhibition of aggregation of the Aβ protofibril by RR-AFC at the molecular level. Molecular docking analysis shows that RR-AFC binds to chain A of the Aβ protofibril through hydrogen bonding interactions. Comparative molecular dynamics simulations depict the binding of RR-AFC at the edge of chain A, and its partially inserted conformation at the hydrophobic core destabilizes the Aβ protofibril. Its binding causes loss of hydrophobic contacts, leading to a partial opening of tightly packed β-sheet protofibrils. The hydration effect of salt bridge between the amino group of Lys28 and the oxygen atom of RR-AFC contributes in destabilization of Aβ protofibrils. Binding free energy calculations of RR-AFC and the Aβ protofibril showed that van der Waals interactions are dominant over the others. Thus, our results revealed that RR-AFC interacts mainly with the hydrophobic core along with positively charged residues of the Aβ protofibril for effective destabilization. Thus, this structural information could be useful to design new inhibitors to control the aggregation of Aβ protofibrils in AD patients.

Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

“…Homology modelling and molecular docking techniques have been found useful to investigate folding pattern and molecular interactions between several enzymes and ligands [33][34][35][36][37][38][39][40][41][42] Binding affinities of Camostat mesylate, Nafamostat and Bromhexine hydrochloride to the active site of modelled protein, TMPRSS2 were confirmed by Autodock 4.2 computational tool with Lamarckian Genetic Algorithm (LGA) [43]. Here, also blind docking was performed by taking protease domain in grid box.…”

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.…”

“…They also showed that it destabilize the protobril by disrupting the native inter-chain D23-K28 salt bridges, decreasing inter-chain backbone hydrogen bonds and rearranges the tightly compact b-strand-bend-b-strand motifs by increasing the interchain A21-V36 distance. In another study, Barale et al 87 showed that binding of arginine hybrid peptides to Abeta protobril destabilize it by breaking of important salt bridge between D23-K28. Gupta et al 65 showed the destabilization ellagic acid (REF) using molecular dynamic simulations.…”

“…86 Thus, the interchain distance between the hydrophobic residues Ala21 and Val36, which is one of the important parameters that determine the destabilization of Abeta protobril, was calculated. 67,87 Fig. 8 shows the average interchain distance between Ala21 (chain A)-Val36 (chain B).…”

Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

“…Homology modelling and molecular docking techniques have been found useful to investigate folding pattern and molecular interactions between several enzymes and ligands [33][34][35][36][37][38][39][40][41][42] AutoDock and UCSF chimera [31].…”