Studying The Effect Of Albumin On The Structure Of Amyloid-β Peptide With Molecular Dynamics Simulations

In recent years,molecular dynamics(MD)has become more widely used in protein studies.At atomic level,MD shows its unique advantages.With an enhanced sampling MD method,this study explores the changes of phase space of an Alzheimer’s diseasecausing peptide after binding to its endogenous inhibitory protein partner.As the most common neurodegenerative disease,Alzheimer’s disease is closely related to the fibrosis of amyloid-β(Aβ)in brain.The key endogenous inhibitor for Aβaggregation is human serum albumin(HSA).In vitro HSA inhibits Aβ fibrillization and targets multiple species along the aggregation pathway(monomers,low molecular weight oligomers and fibrils).Amyloid inhibition by HSA has both pathological significance and therapeutic potential.At present,its potential molecular mechanism has not been studied clearly.As the first step to solve this complex problem,this work uses molecular dynamics to study the interaction between Aβ42 monomer and HSA.Aβ42 is an intrinsically disordered peptide with a relatively flat potential energy surface.It is difficult for conventional molecular dynamics simulations to fully sample its phase space.For this reason,we adopted the replica exchange with solute tempering(REST)method to selectively heat the Aβ42 peptide in the absence and presence of HSA.The simulation results show that Aβ42 binds to multiple locations near HSA domain III and adopts various conformations that all differ from the free state.HSA reduces the β-sheet abundances of H14-E22 and A30-M33 fragments in Aβ42,and shifts its conformational ensemble towards more disordered states.The β-sheet association patterns are changed by HSA,and the β-sheet lengths are also reduced.In particular,the frequent association of Q15-V24 and N27-V36 regions into β-hairpin which is critical for aggregation is impeded.We found that HSA tends to form promiscuous interactions with Aβ42.It is characterized by salt bridges at the edge of the peptide-protein interface and hydrophobic cores at the center.Consequently,intrapeptide interactions crucial for β-sheet formation are disrupted.Our work builds the bridge between the modification of Aβ conformational ensemble and amyloid inhibition by HSA.It also illustrates the potential of the REST method in studying interactions between intrinsically disordered peptides and globular proteins.