| Amyloid peptide?A??is a common neurodegenerative disease,and the aggregation of?-Amyloid peptide is the key to the pathology of AD.pH can affect the aggregation of A?.We use molecular dynamic simulation to study the effect of pH caused on A?42 monomer,the aggregation of A?40/42,oligomers?taken trimer and pentamer as examples?and morphologies of fibrils at atomic level.As the building blocks of fibril,the self-folding and further A?-A?assembly is susceptive to pH.A pH mediatory unfolding effect on A?is observed.pH 6.0,as a threshold,when pH<6.0,the?-helix content goes down as pH goes down with the increase of?-sheet,indicating a conversion from?-helix to?-sheet;while pH>6.0,just goes up with the?-sheet content keeps constant,indicating a conversion from coil to?-helix.Hence change in pH can mediate conversion between?-helix and?-sheet in A?42 monomer,which represents a promising approach to understanding the molecular basis of Alzheimer's disease and opens many perspectives for the design of molecules that are able to interfere with aggregation process.In pH 4.0-7.5,His6/13/14 is protonated in turn and can make itself more acidic.Hence it moves towards the mass center of A?42 monomer.The more acidic of the His,the closer to the mass center.So does for Glu22.When pH?5.0-5.5,the?-sheet content is sharply increased and constrains the movement of Glu22.Taken together,protonation can make negative charged residue more acidic and subsequently move to the MCA.If more?-sheet content generated?i.e.,>30%?,such movement would be confined.The result indicates that three histidines in turn play key inducement roles to the A?42 folding dynamics,and elucidates the significance of N-terminus?especially those charged residues?in A?folding?aggregation?for the first time.A plausible interpretation is offered for the roles of pI?5.0-5.5?and pH 6.0,which are both debated as the most favorable pH conditions for A?aggregation.The present data suggests that at pH 6.0,the net charge of His6-His14 loop becomes zero,indicative of the most open.His13 forms double-salt-bridges with Glu22 and put the whole?1 sequence?17-26?"linearly"in solution,greatly favorable to the A?-A?self-assembly in register.At pI,the net charge of whole A?42 monomer becomes zero and?-sheet content is about twice compared with that of pH 6.0 system.The monomer consists of four?-strands and looks like a ball.Besides,part of NT involves exclusively in?-strand.Therefore pI is favorable to A?-A?intermolecular aggregation.These findings enrichs the interpretation for why lower pH favors the A?self-folding and A?-A?aggregation.Trimer is the smallest oligomer,which can preserves preformed fibroid architecture under different pHs.Different from the intense impact on A?42 monomer,pH does not change a mass of contents of oligomeric secondary structures,interchain distance and number of H-bond in?core.But we finds when Asp23-Lys28 forms salt-bridges,the pK value of Asp23is depressed and the pK value of Lys28 is elevated.When Lys28 is indeed exposed to the bulk water or H-bonds with adjacent residues,its pK value is in normal range.Hence we propose a pK prediction method,by which one can assess the stability of a preformed fibril by simply measuring its pK and compared it with its normal value.The method is confirmed applicable to the present amyloid fibril and insulin fibril,and expected to extend into other protein fibrils.We probe the effect of pH 1.5,3.0 and 7.5 on A?42 fibrils with different layers and find that there are no obvious difference among the secondary content,number of H-bond and interchain distance in?core region,indicating the effect of pH on?core region is small.12,14 and 15 layers are established to be the smallest realistic models for A?42 fibrils at pH 1.5,3.0 and 7.5,respectively,with twist angles of 0.40°,0.34°,0.31°,disclosing the positive effect of the strong acidity on the fibril twist.The presence of salt can screen electrostatic repulsion between negative charges of A?fibril,similar to protonation caused by lowering pH.Hence both salt and lowing pH can increase the twist of fibril.In addition,we find that NT can hamper the tragger between?1 and?2 strands and prevents further twist of fibril at neutral condition,indicating NT importance to the stability of these fibrils and acting as the potential regulatory region of A?42 fibril.Additionally,we study the effect of His isomers caused on the oligomerization of A?40/42.The A?40?????5 system tends to form small oligomers such as monomer,dimer and trimer in first 50 ns and tends to form pentamer in following simulations.The A?40?????5 system tends to form small oligomers in first 200 ns,a period much longer than?????5 system.This indicates that His isomer can accelerate the stage of forming small oligomers.So does for A?42 systems.The A?42?????5 system tends to form pentamer after 50 ns while the?????5system is in a phase where the fluctuation keeps almost constant and tetramer and monomer assemble into pentamer in latter period. |
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