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The Stability and Dynamics of the Human Calcitonin Amyloid Peptide DFNKF

Hui-Hsu (Gavin) Tsai ^*, David Zanuy , Nurit Haspel , Kannan Gunasekaran ^*, Buyong Ma ^*, Chung-Jung Tsai ^* and Ruth Nussinov ^* 

^* Basic Research Program, Science Applications International Corporation-Frederick, Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick, Maryland 21702; Laboratory of Experimental and Computational Biology, National Cancer Institute, Frederick, Maryland 21702; School of Computer Science, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel; and Sackler Institute of Molecular Medicine, Department of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence: Address reprint requests to Ruth Nussinov, Tel.: 301-846-5579; Fax: 301-846-5598; E-mail: ruthn{at}ncifcrf.gov.

The stability and dynamics of the human calcitonin-derived peptide DFNKF (hCT_15–19) are studied using molecular dynamics (MD) simulations. Experimentally, this peptide is highly amyloidogenic and forms fibrils similar to the full length calcitonin. Previous comparative MD studies have found that the parallel ß-stranded sheet is a stable organization of the DFNKF protofibril. Here, we probe the stability and dynamics of the small parallel DFNKF oligomers. The results show that even small DFNKF oligomers, such as trimers and tetramers, are stable for a sufficient time in the MD simulations, indicating that the crucial nucleus seed size for amyloid formation can be quite small. The simulations also show that the stability of DFNKF oligomers increases with their sizes. The small but stable seed may reflect the experimental rapid formation of the DFNKF fibrils. Further, a noncooperative process of parallel ß-sheet formation from the out-of-register trimer is observed in the simulations. In general, the residues of DFNKF peptides near the N-/C-termini are more flexible, whereas the interior residues are more stable. Simulations of mutants and capped peptides show that both interstrand hydrophobic and electrostatic interactions play important roles in stabilizing the DFNKF parallel oligomers. This study provides insights into amyloid formation.

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