Molecular Mechanism Of Conformational Transition Of Aβ42 Inhibited By GV971 And Ulvan Components

Alzheimer’s disease(AD)is the most common form of dementia.The misfolding of amyloid-β(Aβ)leads to aggregation into toxic aggregates rich in β-sheet,which ultimately leads to the death of nerve cells and leads to AD,which is considered to be the main idea of the amyloid cascade hypothesis.The conformational transition from α-helix or random coil to β-sheet of Aβ monomer is crucial in the amyloid cascade hypothesis.Inhibiting the misfolding of Aβ monomer and maintaining its initial conformation is an attractive strategy for the treatment of AD.Therefore,it is very important to investigate the molecular mechanism of inhibition of Aβ conformational transition by existing inhibitors.GV971 derived from marine acid oligosaccharides was conditionally approved for the treatment of patients with mild to moderate AD,but the mechanism of its inhibition of Aβconformational transition remains unclear.In order to solve this problem,molecular dynamics simulation was used to investigate in detail the molecular mechanism of GV971 components Di M,Tetra M,Hexa M and Octa M inhibiting the conformational transition of Aβ42 monomer.The results showed that GV971 inhibited conformational transformation and hydrophobic collapse of Aβ by maintaining the helix structure and inhibiting the formation of β-sheet structure.Binding energy analysis showed that both electrostatic energy and Van der Waals energy were beneficial to the binding of GV971 components to Aβ42 monomer.Among them,electrostatic interaction energy plays a dominant role(> 85%).GV971 components directly interact with charged residues D1,R5,K16 and K28 to form hydrogen bonds and salt bridges,which specifically bind to the N-terminal region of Aβ42.In addition,ulvan,also from marine algae,were found to inhibit the fibrosis process of Aβ and reduce its cytotoxicity in our earlier studies.Ulvan,like GV971,may be an effective drug for curing AD.Although detailed experimental studies have been carried out on ulvan,the mechanism of inhibition of Aβ conformation transition is still unclear.Therefore,the theoretical models of four common ulvan units,U2s3 s,U3s,A3 s and B3 s,were constructed,and the molecular dynamics simulation was used to investigate their inhibition mechanism of Aβ42 conformational transition.The results showed that the ulvan units could inhibit the conformational transition from α-helix to β-sheet and hydrophobic collapse of Aβ.And ulvan unit bond to the N-terminal region and C-terminal region of Aβ42 monomer by strong electrostatic interaction(> 80%)and van der Waals interaction,forming many hydrogen bonds with charged residues on Aβ to destroy the internal interactions,thus inhibiting the conformational transition of Aβ.In addition,comparing the structural parameters of Aβ,it was found that the order of inhibitory effect of ulvan units was U2s3 s ≈ A3 s ≥ U3 s > B3 s.Finally,the comparison between Di M and ulvan units showed that ulvan units containing sulfate group had more advantages in inhibiting the conformational transition of Aβ.These results are helpful to understand the molecular mechanism of inhibition of Aβ conformational transition by GV971 components and ulvan,which is beneficial to the development of high effective sugar inhibitors against AD.