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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Molecular Dynamics of Amylin Amyloid Single and MultipleBeta SheetsDmitrijs Lapidus 1 , Salvador Ventura 2 , Cezary Czaplewski 3 ,Adam Liwo 3 , and Inta Liepina 11 Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga, LV1006, Latvia; 2 Institutde Biotecnologia i de Biomedicina, Universitat Autonoma de Barcelona, E-08193,Bellaterra, Spain; 3 Department of Chemistry, and University of Gdansk, ul. Sobieskiego 18,80-952, Gdansk, PolandIntroductionAmyloidosis is progressive metabolic conformational disease caused by misfolding andaggregation of soluble proteins in insoluble fibrils which impair cell functioning or cell-tocellconnectivity [1]. Amylin or Islet Amyloid Polypeptide (IAPP) is a 37 residue peptidehormone secreted by pancreatic -cells. Amylin forms deposits in pancreas and is a noninsulin-dependenttype II diabetes disease agent [2].Six-stranded single -sheets of amylin 10-29 (Amyl 10-29),Gln 10 -Arg 11 -Leu 12 -Ala 13 -Asn 14 -Phe 15 -Leu 16 -Val 17 -His 18 -Ser 19 -Ser 20 -Asn 21 -Asn 22 -Phe 23 -Gly 24 -Ala 25 -Ile 26 -Leu 27 -Ser 28 -Ser 29reverse amylin 10-29 (RevAmyl 10-29)Ser 10 -Ser 11 -Leu 12 -Ile 13 -Ala 13 -Gly 15 -Phe 16 -Asn 17 -Asn 18 -Ser 19 -Ser 20 -His 21 -Val 22 -Leu 23 -Phe 24 -Asn 25 -Ala 26 -Leu 27 -Arg 28 -Gln 29and a scrambled version (ScrambAmyl 10-29),Leu 10 -Ile 11 -Gln 12 -Ser 13 -Ala 14 -Phe 15 -Gly 16 -Asn 17 -Val 18 -Asn 19 -His 20 -Leu 21 -Ser 22 -Arg 23 -Phe 24 -Asn 25 -Ser 26 -Ser 27 -Ala 28 -Leu 29as well as six -sheet stacks 6xAmyl 10-29, 6xRevAmyl 10-29, 6xScrambAmyl 10-29(Figure 1), of the all three systems were simulated by molecular dynamics (MD) withAmber 9.0, f99 force field, NTP protocol (constant number of particles, temperature,pressure), using a periodic water box of explicit water molecules 5 Å layer over the solutefor single -sheets and 10 Å layer for the -sheet stacks. The systems were supplementedby chlorine counterions for the neutral charge. For single -sheets the system temperaturewas raised stepwise from 10 K to 309 K in 40 ns of the MD run, then the systems weresimulated at the temperature of 309 K. The total MD run was 187 ns for Amyl 10-29, 140ns for RevAmyl 10-29 and 116 ns for ScrambAmyl 10-29. The -sheet stack MDs werestarted from 309 K, and the simulation time is 41 ns for 6xAmyl 10-29, 38 ns for6xRevAmyl 10-29 and 39 ns for 6xScrambAmyl 10-29.Results and DiscussionSingle -sheets. All three systems show stable single -sheet structures. Amyl 10-29ß-sheet stretches across the regions Arg 11 -Val 17 and time to time expands till Ser 19 , besidestwo strands have stable -sheet over the region Asp 22 -Leu 27 . In the Amylin 10-29 regionSer 19 -Ser 20 -Asn 21 -Asn 22 the -sheet has W-shaped bend with the deeper vertex on Ser 20 andsmaller vertex on Asn 22 , suggesting that also the bent -sheet could be possible. Apart frombackbone hydrogen bonding the -sheets of Amyl 10-29 are stabilized by side chainhydrogen bonding between asparagine residues and between residues Ser 20 and Asp 22 . The-sheets of Amyl 10-29 are glued together by leucine, isoleucine, valine residues and byphenylalanine residues, which together with asparagine residues form a sub-stack kepttogether by mild polar interactions. The -sheet of the backward amylin RevAmyl 10-29 ismore flat and stronger than that one of Amyl 10-29. -sheet of the scrambled amylinScrambAmyl 10-29 is strong, suggesting that for this sequence the order of amino acids isnot important regarding the capability to create the -sheet.The distances between the mass centers of the nearby amino acid residues is of thesame magnitude for the Amylin10-29 -sheet and the RevAmyl 10-29, confirming that thealteration of the direction of the peptide chain does not change the compactness of the-sheet.570