TY - JOUR
T1 - The sequence dependence of fiber organization. A comparative molecular dynamics study of the islet amyloid polypeptide segments 22-27 and 22-29
AU - Zanuy, David
AU - Nussinov, Ruth
N1 - Funding Information:
We thank Drs B. Ma, K. Gunasekaran, C. -J. Tsai and S. Kumar for discussions. In particular, we thank Dr Jacob V. Maizel for encouragement. The computation times are provided by the National Cancer Institute's Frederick Advanced Biomedical Supercomputing Center and by the NIH Biowulf. The research of R. Nussinov in Israel has been supported, in part, by the Magnet grant, by the Ministry of Science grant, and by the “Center of Excellence in Geometric Computing and its Applications” funded by the Israel Science Foundation (administered by the Israel Academy of Sciences), and by the Adams Brain Center. This project has been funded, in whole or in part, with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12400. The content of this publication does not necessarily reflect the view or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government.
PY - 2003/6/6
Y1 - 2003/6/6
N2 - Amyloid fiber formation and the possible polymorphism of molecular arrangements depend on the polypeptide length and composition. Here, we seek the chemical clues underlying these processes. Our starting point is based on the experimental observation that some short peptide segments are able to develop fibers that are very similar to those of their original parent proteins. We focus our study on the NFGAILSS peptide, derived from the human islet amyloid polypeptide (residues 22-29). This peptide turned out to be a perfect example, illustrating the fact that the amyloid microscopic organization is highly complex, rather than simply involving hydrogen bond formation. Furthermore, obtaining a reliable molecular model has allowed us to analyze the differences between the amyloid structure we have obtained for this peptide and that obtained for the previously studied, two residues shorter, segment (residues 22-27, NFGAIL). This comparative study yields some clues about chemical events that govern the aggregation of proteins into oriented fibers, such as molecular packing between sheets and the degree of interaction specificity. We characterize the important role played by the hydrophobic and aromatic residues in the inter-sheet association and present new approaches toward the understanding of the nature of events that are likely to take place during fibril formation. These include analysis of interaction patterns derived from specific sheet-associated packing.
AB - Amyloid fiber formation and the possible polymorphism of molecular arrangements depend on the polypeptide length and composition. Here, we seek the chemical clues underlying these processes. Our starting point is based on the experimental observation that some short peptide segments are able to develop fibers that are very similar to those of their original parent proteins. We focus our study on the NFGAILSS peptide, derived from the human islet amyloid polypeptide (residues 22-29). This peptide turned out to be a perfect example, illustrating the fact that the amyloid microscopic organization is highly complex, rather than simply involving hydrogen bond formation. Furthermore, obtaining a reliable molecular model has allowed us to analyze the differences between the amyloid structure we have obtained for this peptide and that obtained for the previously studied, two residues shorter, segment (residues 22-27, NFGAIL). This comparative study yields some clues about chemical events that govern the aggregation of proteins into oriented fibers, such as molecular packing between sheets and the degree of interaction specificity. We characterize the important role played by the hydrophobic and aromatic residues in the inter-sheet association and present new approaches toward the understanding of the nature of events that are likely to take place during fibril formation. These include analysis of interaction patterns derived from specific sheet-associated packing.
KW - Amyloid conformation
KW - Islet amyloid peptide
KW - Molecular dynamics simulation
KW - Protein unfolding
KW - β-sheet
UR - http://www.scopus.com/inward/record.url?scp=0038274079&partnerID=8YFLogxK
U2 - 10.1016/S0022-2836(03)00491-1
DO - 10.1016/S0022-2836(03)00491-1
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AN - SCOPUS:0038274079
SN - 0022-2836
VL - 329
SP - 565
EP - 584
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 3
ER -