Structural Stability and Dynamics of an Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35 Export

@article{citeulike:3726924, abstract = {A seven amino acid yeast prion sup-35 fragment (GNNQQNY) forms amyloid fibrils. The availability of its detailed atomic oligomeric structure makes it a good model for studying the early stage of aggregation. Here we perform long all-atom explicit solvent molecular simulations of various sizes and arrangements of oligomer seeds of the wild-type and its mutants to study its stability and dynamics. Previous studies have suggested that the early stage rate-limiting step of oligomer formation occurs in high-order oligomers. Our simulations show that with the increase in the number of strands even from a dimer to a trimer, oligomer stability increases dramatically. This suggests that the minimal nucleus seed for GNNQQNY fibril formation could be small and is likely three or four peptides, in agreement with experiment, and that higher-order oligomers do not dissociate quickly since they have small diffusion coefficients and thus slow kinetics. Further, for the hydrophilic polar GNNQQNY, there are no hydrogen bonds and no hydrophobic interactions between adjacent {beta}-sheets. Simulations suggest that within the sheet, the driving forces to associate and stabilize are interstrand backbone-backbone and side chain-side chain hydrogen bonds, whereas between the sheets, shape-complementary by the dry polar steric zipper via the side chains of Asn-2, Gln-4, and Asn-6 holds the sheets together, as proposed in an earlier study. Since the polar side chains of Asn-2, Gln-4, and Asn-6 act as a hook to bind two neighboring sheets together, these geometric restraints reduce the conformational search for the correct side chain packing to a two-dimensional problem of intersheet side chain interactions. Mutant simulations show that substitution of Asn-2, Gln-4, or Asn-6 by Ala would disrupt this steric zipper, leading to unstable oligomers. 10.1529/biophysj.106.083246}, author = {Zheng, Jie and Ma, Buyong and Tsai, Chung-Jung and Nussinov, Ruth}, citeulike-article-id = {3726924}, citeulike-linkout-0 = {http://dx.doi.org/10.1529/biophysj.106.083246}, citeulike-linkout-1 = {http://www.biophysj.org/cgi/content/abstract/91/3/824}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16679374}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16679374}, day = {1}, doi = {10.1529/biophysj.106.083246}, journal = {Biophys. J.}, keywords = {amyloids, short-peptides}, month = {August}, number = {3}, pages = {824--833}, posted-at = {2008-11-29 13:13:20}, priority = {2}, title = {Structural Stability and Dynamics of an Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35}, url = {http://dx.doi.org/10.1529/biophysj.106.083246}, volume = {91}, year = {2006} }

TY - JOUR ID - citeulike:3726924 L3 - citeulike-article-id:3726924 N2 - A seven amino acid yeast prion sup-35 fragment (GNNQQNY) forms amyloid fibrils. The availability of its detailed atomic oligomeric structure makes it a good model for studying the early stage of aggregation. Here we perform long all-atom explicit solvent molecular simulations of various sizes and arrangements of oligomer seeds of the wild-type and its mutants to study its stability and dynamics. Previous studies have suggested that the early stage rate-limiting step of oligomer formation occurs in high-order oligomers. Our simulations show that with the increase in the number of strands even from a dimer to a trimer, oligomer stability increases dramatically. This suggests that the minimal nucleus seed for GNNQQNY fibril formation could be small and is likely three or four peptides, in agreement with experiment, and that higher-order oligomers do not dissociate quickly since they have small diffusion coefficients and thus slow kinetics. Further, for the hydrophilic polar GNNQQNY, there are no hydrogen bonds and no hydrophobic interactions between adjacent {beta}-sheets. Simulations suggest that within the sheet, the driving forces to associate and stabilize are interstrand backbone-backbone and side chain-side chain hydrogen bonds, whereas between the sheets, shape-complementary by the dry polar steric zipper via the side chains of Asn-2, Gln-4, and Asn-6 holds the sheets together, as proposed in an earlier study. Since the polar side chains of Asn-2, Gln-4, and Asn-6 act as a hook to bind two neighboring sheets together, these geometric restraints reduce the conformational search for the correct side chain packing to a two-dimensional problem of intersheet side chain interactions. Mutant simulations show that substitution of Asn-2, Gln-4, or Asn-6 by Ala would disrupt this steric zipper, leading to unstable oligomers. 10.1529/biophysj.106.083246 IS - 3 JF - Biophys. J. EP - 833 TI - Structural Stability and Dynamics of an Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35 VL - 91 SP - 824 KW - amyloids KW - short-peptides AU - Zheng, Jie AU - Ma, Buyong AU - Tsai, Chung-Jung AU - Nussinov, Ruth PY - 2006/08/01/ UR - http://dx.doi.org/10.1529/biophysj.106.083246 ER -