Published: August 25, 2011 r2011 American Chemical Society 11137 dx.doi.org/10.1021/jp2046454 | J. Phys. Chem. B 2011, 115, 11137–11144 ARTICLE pubs.acs.org/JPCB Dewetting Transitions in the Self-Assembly of Two Amyloidogenic β-Sheets and the Importance of Matching Surfaces Zaixing Yang, † Biyun Shi, † Hangjun Lu, ‡ Peng Xiu,* ,† and Ruhong Zhou* ,§ † Bio-X Lab, Department of Physics, and Soft Matter Research Center, Zhejiang University, Hangzhou 310027, China ‡ Department of Physics, Zhejiang Normal University, 321004, Jinhua, China § Computational Biology Center, IBM Thomas J. Watson Research Center, 1101 Kitchawan Road, Yorktown Heights, New York 10598, United States b S Supporting Information ABSTRACT: We use molecular dynamics simulations to investigate the water-mediated self-assembly of two amyloidogenic β-sheets of hIAPP 22À27 peptides (NFGAIL). The initial configurations of β-sheet pairs are packed with two different modes, forming a tube-like nanoscale channel and a slab-like 2-D confinement, respectively. For both packing modes, we observe strong water drying transitions occurring in the intersheet region with high occurrence possibilities, suggesting that the “dewetting transition”-induced collapse may play an important role in promoting the amyloid fibrils formation. However, contrary to general dewetting theory prediction, the slab-like confinement (2-D) shows stronger dewetting phenomenon than the tube-like channel (1-D). This unexpected observation is attributed to the different surface roughness caused by different packing modes. Furthermore, we demonstrated the profound influence of internal surface topology of β-sheet pairs on the dewetting phenomenon through an in silico mutagenesis study. The present study highlights the important role of packing modes (i.e., surface roughness) in the assembly process of β-sheets, which improves our understanding toward the molecular mechanism of the amyloid fibrils formation. In addition, our study also suggests a potential route to regulate controllably the self-assembly process of β-sheets through mutations, which may have future applications in nanotechnology and biotechnology. ’ INTRODUCTION Hydrophobic interactions play an important role in many important chemical and biophysical phenomena, such as protein folding, misfolding, and aggregation, 1À6 ligand binding, 7À9 self- assembly of amphiphiles, 10,11 and gating of ion channels. 12,13 In some extreme cases, the hydrophobic interaction is so strong that there exists a so-called nanoscale dewetting (water drying) transition; 14À16 that is, when two nanoscale hydrophobic objects (plates) approach each other and reach a critical distance, often large enough to accommodate several layers of water molecules, the water molecules in the interface region are expelled in a very short period of time (∼100 ps) before the collapse of two plates. The presence and significance of such drying transitions have been investigated in both physical 15,17À19 and biological systems. 5À7,15,20À22 For example, in a previous study, we found a strong water drying transition inside the nanoscale channel (1-D like) formed by the protein melittin tetramer, with a channel size of up to 2 to 3 water diameters. 22 There is no dewetting transition found during the two-domain enzyme pro- tein BphC collapse, despite the very strong hydrophobic inter- faces between the two domains (2-D like). 5 These studies indi- cate that even in the presence of the polar protein backbone a high confinement environment (1-D like), together with suffi- ciently hydrophobic protein surfaces, can induce a liquidÀvapor Received: May 18, 2011 Revised: August 24, 2011