TY - JOUR
T1 - Peptide sequence and amyloid formation
T2 - Molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs
AU - Zanuy, David
AU - Porat, Yair
AU - Gazit, Ehud
AU - Nussinov, Ruth
N1 - Funding Information:
We thank Drs. K. Gunasekaran, S. Kumar, B. Ma, C.-J. Tsai, and G. Tsai 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.N. in Israel has been supported in part 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. The research of E.G. has been supported in part by a start-up grant from the US-Israel Binational Science Foundation (BSF-2000337). 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 U. S. Government.
PY - 2004/3
Y1 - 2004/3
N2 - We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues.
AB - We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues.
UR - http://www.scopus.com/inward/record.url?scp=1542686314&partnerID=8YFLogxK
U2 - 10.1016/j.str.2004.02.002
DO - 10.1016/j.str.2004.02.002
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AN - SCOPUS:1542686314
SN - 0969-2126
VL - 12
SP - 439
EP - 455
JO - Structure
JF - Structure
IS - 3
ER -