Inhibition And Disassembly Effect Of Drug Molecules On A?42 Aggregates

Alzheimer's disease?AD?is characterized by fibrillar deposits of amyloid-??A??peptides and neurofibrillary tangles of Tau proteins.A?peptides are composed of 37 to 49 residues,in which the A?42 is highly toxic and easy to aggregate and A?40 is the most abundant.Therefore,the study on aggregation processes,mechanisms and modulation of A?40 and A?42 is very critical.The study is composed of three parts,in which aggregation and inhibition/dissambly mechanisms of A?monomers,oligomers,fibers are discussed by introducing separately the natural drugs chloroiodine?CQ?,tanshinone?TS?,erythrosine B?ER?and their derivatives.The study scheme for each part is processed through the construction of force fields,handling of docking,and simulation analysis,etc.In monomers,the drugs have inhibitory effect on the misfolding of Cu²⁺-induced A?42monomers in three different pH values?Ia-??,IIa-???and IIa-????.The fluctuation of RMSD and secondary structure is mainly affected by the?2 region.The presence of the drugs not only inhibits the conversion of coil/turn to?-sheet in Ia-??model,but also promotes the reverse conversion of coil/turn to helix.The binding energy??E_b?is divided into two types:positive and negative ones.For the negative?E_b,?E_vdw is the determinant contibutor.The neutral drugs CQ has the strongest binding energy at high pH.For the systems with positive?E_b,ER increases the helix structure of all systems and has stronger effect than TS in Ia-??model.However,when ER is added to IIa-???model,its binding energy shows a negative value?-22.5 kJ/mol?.Compared with the negative value of other systems,it is much smaller.ER mainly locates on the surface of DR region.The electrostatic repulsion and hydrophobic effect make it difficult to contact the two terminal residues of DR and?2.For example,ERs prefer to contacting the key residues H13/H14 with Cu²⁺coordination in IIa-???model,in which positively charged Cu²⁺neutralizes part of the electrostatic repulsion,leading to negative binding energy and reflecting the important synergy of Cu²⁺.Neutral drugs inhibit A?aggregation through hydrophobic interaction,?-?stacking,and hydrogen bonding.On the one hand,they interact with K16/F19/L34,the key residues in seeding protofibrils,and subsequently preventing monomers aggregation and growth to form fiber.On the other hand,if neutral drugs can insert into disordered A?-Cu²⁺structures,then the number of contacts between the drug and the surrounding residues will be formed,and the corresponding binding energy will also increase.In oligomers,as the intrinsic origin of A?hypothesis to form AD,histidine behaviors were emerged to play a crucial role in A?aggregation.To investigate the histidine behaviors in early stage for aggregation,A?40/42 pentamers with different histidine isomer states were simulated at the atomic level.Results show that five?????₄₀ and?????₄₂2 monomers can rapidly promote stable pentamer formation.?????₄₀ and?????₄₂ can form stable oligomers quickly in the early stage.?????₄₀ and?????₄₂ changed the aggregation path and directly aggregated into abundant?-sheet pentamers.After adding the drug,the reduction of?-sheet and hydrogen bond further indicated that any of these drugs can inhibit the aggregation of oligomers and the drugs mainly reduce secondary structure in the initial stage,while changing the structure in the later stage.The binding energy results show that different structures lead to different binding energy for the same drug.Among the oligomers,?????₄₀ and?????₄₂ have more?-sheet,so they have stronger rigidity and electrostatic repulsion.The DLVO theory is applicable to the ER-oligomer system,if the ER concentration is low enough and the ER happens to contact positively charged residues,their binding energy will be negative.For structural changes,?????₄₀ and?????₄₂ are better than the pentamers with histidine variant?s?.ER mainly interacts with the charged residues of oligomers,and the effect of ER in?????₄₂2 is better than in?????₄₀ due to the role of histidine tautomerization in the aggregation process.The results of both our histidine tautomerization and drug inhibition can expand our understanding of AD generation and modulation and may open a new door for understanding the AD tautomerism hypothesis.In fibers,we capture the atomic-level details of the interactions between sigmoid A?42fibril 2MXU/5KK3 and either natural tanshinone compounds TS1/TS0 or negative charged ER,proposing two unprecedented disassembly mechanisms.Natural TS1/TS0 prefers to insert into the cavity together with part at the surface of the 2MXU to open up the mouth and twist the conformation,destroying the ordered growth of subsequent monomers along the fibril axis.For the more compact two-fold 5KK3,attachment of TS1/TS0 at the surface including some inserted in cavity results in the separation of the two folds.In the two sigmoid fibril systems,it is no longer applicable for the routine criterions to assess A?42 fibril disassembly by introduction of these drugs,such as either reduced H-bond number,decreased?-sheet contents or both.ER,like-charged to A?42 fibril,is especially exceptional,and departs utterly from the neutral ones in disassembly A?42 fibril.Besides of the inapplicable routine criterions,positive binding energy between ER and A?42 fibril also deviates from hypotheses of“ligands exhibiting greater affinity for the?-amyloid peptide are effective at altering its aggregation and inhibiting cell toxicity”,but resulting in stronger disassembly effect on the two kinds of sigmoid A?42 fibrils than neutral TS0/TS1.The disassembly power of charged ER derives from its stronger deformation ability to the conformation of A?42 fibril than the neutral ones,twisting the one-fold 2MXU in tapered-shape and separating two-fold5KK3 in two parts more further,that is in great consistence with experimental observations.Current results not only deepen one insight into the inhibition and disaggregation effects of both natural and charged drug molecules on A?aggregates,but also orientate the development and design of new drugs in the future.