The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of...The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of hlAPP are analyzed. Particularly, the conformational changes of the amyloidogenic-related regions of residues 15-- 17 and 20--29 are emphasized. Our studies find that, for WT hlAPP, residues 15--17 always maintain a stable a-helix structure, residues 20--25 structurally fluctuate between turn and 5-helix, and residues 26--29 mainly adopt coil and bend structures. The hydrogen bonds between the polar groups of hlAPP, long-rang van der Waals forces between the residues, and hydrophobic interactions between the residues of hlAPP are important driving forces to maintain the secondary structure of hlAPP. The replacement of leucine 16 by glutamine stabilizes the helix structure of residues 15--17 and 20--23 of hlAPP monomer, and the structure of residues 24--29 fluctuates be- tween helix and turn. The relatively stable helix structures of residues 15--17 and 20--29 are supposed to be beneficial for L16Q hlAPP to resist the aggregation as observed in the experiment. The substitution of serine20 by glycinc drives residues 15--17 and 20--29 of hlAPP to transform from helix structure to β-strands or coil structures with higher extension and flexibility, which may promote the aggregation of hlAPP as the experiments reported. These results are significant to understand the aggregation mechanism of hlAPP monomer into the dimer, trimer, oligomers and fibrils associated with the type 2 diabetes at the atomic level.展开更多
文摘The conformation change picture of human islet amyloid polypeptide （hlAPP） is outlined using molecular dynamics simulation, and the structural influences of L16Q, S20G, and L16Q-S20G mutations on the conformation of hlAPP are analyzed. Particularly, the conformational changes of the amyloidogenic-related regions of residues 15-- 17 and 20--29 are emphasized. Our studies find that, for WT hlAPP, residues 15--17 always maintain a stable a-helix structure, residues 20--25 structurally fluctuate between turn and 5-helix, and residues 26--29 mainly adopt coil and bend structures. The hydrogen bonds between the polar groups of hlAPP, long-rang van der Waals forces between the residues, and hydrophobic interactions between the residues of hlAPP are important driving forces to maintain the secondary structure of hlAPP. The replacement of leucine 16 by glutamine stabilizes the helix structure of residues 15--17 and 20--23 of hlAPP monomer, and the structure of residues 24--29 fluctuates be- tween helix and turn. The relatively stable helix structures of residues 15--17 and 20--29 are supposed to be beneficial for L16Q hlAPP to resist the aggregation as observed in the experiment. The substitution of serine20 by glycinc drives residues 15--17 and 20--29 of hlAPP to transform from helix structure to β-strands or coil structures with higher extension and flexibility, which may promote the aggregation of hlAPP as the experiments reported. These results are significant to understand the aggregation mechanism of hlAPP monomer into the dimer, trimer, oligomers and fibrils associated with the type 2 diabetes at the atomic level.
