Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides(NFGAIL) Aggregation

Peptides/proteins aggregation can give rise to pathological conditions of many human diseases.Small partially ordered oligomers formed in the early stage of aggregation,rather than mature fibrils,are thought to be the main toxicity agent for the living cell.Thus,understanding the pathway and the underlying physical mechanism in the early stage of aggregation is very important for prevention and treatment of these protein functional diseases.Herein we use all-atom molecular dynamics simulations to study the aggregation of four NFGAIL hexapeptides(NFGAIL peptide is a core segment of human islet amyloid polypeptide and exhibits similar aggregation kinetics as the full-length polypeptide).We observe that the peptide monomers in water mainly adopt non-structural coil configurations;the four peptides which are randomly placed in water aggregate spontaneously to partially ordered oligomer(β-sheets)through dimerization or trimerization,with the dimerization predominated.Both parallel and anti-parallelβ-sheets are observed.The hydrophobic interactions drive the initial peptides associations,and the subsequent conformational fluctuations promote the formation of more hydrogen bonds between the dangling hydrogen sites in the main chains of peptides.     

Molecular Mechanism of the Early Stage of Amyloidogenic Hexapeptides (NFGAIL) Aggregation

Peptides/proteins aggregation can give rise to pathological conditions of many human diseases. Small partially ordered oligomers formed in the early stage of aggregation, rather than mature fibrils, are thought to be the main toxicity agent for the living cell. Thus, understanding the pathway and the underlying physical mechanism in the early stage of aggregation is very important for prevention and treatment of these protein functional diseases. Herein we use all-atom molecular dynamics simulations to study the aggregation of four NFGAIL hexapeptides (NFGAIL peptide is a core segment of human islet amyloid polypeptide and exhibits similar aggregation kinetics as the full-length polypeptide). We observe that the peptide monomers in water mainly adopt non-structural coil configurations; the four peptides which are randomly placed in water aggregate spontaneously to partially ordered oligomer (β-sheets) through dimerization or trimerization, with the dimerization predominated. Both parallel and anti-parallel β-sheets are observed. The hydrophobic interactions drive the initial peptides associations, and the subsequent conformational fluctuations promote the formation of more hydrogen bonds between the dangling hydrogen sites in the main chains of peptides.