Dynamics and stability of amyloid-like steric zipper assemblies with hydrophobic dry interfaces.
Recent seminal investigations have suggested that the basic structural motif of amyloid fibers may be constituted by a tight association of two facing beta-sheets (steric zipper). Although this model has been derived from crystal structures of small peptide models, several theoretical investigations, essentially focused on steric zipper interface containing large polar and/or aromatic side chains, have confirmed the stability of this motif in a crystal-free context. To analyze the general validity of these findings, we carried out molecular dynamics (MD) simulations on aggregates stabilized by steric zipper interfaces made also of small or hydrophobic residues. In particular, we here characterized assemblies formed by the peptides SSTSAA and VQIVYK, whose structures have been recently solved at high resolution. In contrast to previous results obtained for polar/aromatic aggregates of the same size and with similar interface area, steric zipper assemblies composed of a pair of 10-stranded beta-sheets show high fluctuations and significant distortions in the simulation timescales (40-60 ns). Taking into account the crystal packing, the effect of the addition of an extra sheet to the assemblies was also evaluated. The MD results indicate that this addition does not provide extra-stabilization to the pair of sheet models. Although present data do not preclude the possibility that the steric zipper association identified in the crystal structure is the basic motif of SSTSAA and VQIVYK fibers, our findings highlight the importance of the nature of residues directly involved in the motif. Indeed, polar and aromatic residues that may form intrasheet and intersheet interactions likely provide a strong contribution to the steric zipper motif stability. Along this line, assemblies endowed with hydrophobic residues presumably require larger interfaces. In line with this suggestion, MD analysis of the HET-s(218-289) prion models composed of a similar number of strands shows that the assembly is endowed with a remarkable stability.
Vitagliano
Luigi
L
Istituto di Biostrutture e Bioimmagini, CNR via Mezzocannone 16, I-80134 Napoli, Italy. luigi.vitagliano@unina.it
Stanzione
Francesca
F
De Simone
Alfonso
A
Esposito
Luciana
L
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
D000682:Amyloid