How SLKP peptoid inhibits Aβ42 self-aggregation in Alzheimer’s disease: A molecular dynamics investigation

Abstract

Amyloid-β (Aβ) aggregation, a key pathological hallmark of Alzheimer’s disease (AD) leads to formation of insoluble oligomers and fibrils which gets deposited in interstitial spaces of brain resulting in loss of intellectual functioning of brain. From last decade, peptidomimetically derived peptoids have shown proficient pharmacokinetic properties against AD. Recently, SLKP peptoid, displaying significant neuro-protection and neuro-regeneration against Aβ toxicity and its ability to cross blood brain barrier was reported. The in vivo and in vitro results shows that SLKP inhibit the self-aggregation of Aβ42. However the exact mechanism of inhibition of amyloid aggregation by SLKP is not reported. In this regards, in the present study the molecular mechanism by which SLKP inhibits Aβ42 monomer aggregation has been elucidated using molecular docking and molecular dynamics (MD) simulations. Molecular docking analysis highlights that SLKP shows interaction with the N-terminal region of Aβ42 monomer. To find out the big picture, explicit type MD of Aβ42 monomer alone and in presence of SLKP was performed. MD analysis highlighted that SLKP efficiently obstructed conformational transition and stabilizes the native helical structure of Aβ42 monomer by interacting with N-terminal region, and C-terminal region. The clustering analysis shows the conformations, in which SLKP interact with the N and C-terminal region of Aβ42 monomer, blocking the self-aggregation of Aβ42 monomer form both terminal. Secondary structure analysis shows that SLKP remarkably intensifies the helical content from 5% to 37% in Aβ monomer and prevents the formation of β-sheet structure at C-terminal, which demonstrated the conservation of native structure of Aβ42 monomer in presence of SLKP. MM-PBSA analysis highlighted that Asp7, Ser8, Gly9, His13, Val18 and Ala21 were found to be the key residues of Aβ42 monomer that participated in binding with SLKP. The insights into the underlying inhibitory mechanism of SLKP against Aβ aggregation will be lucrative for peptoid based therapeutics against AD in future.