Engineering complementary hydrophobic interactions to control β-hairpin peptide self-assembly, network branching, and hydrogel properties.

Abstract

The MAX1 β-hairpin peptide (VKVKVKVK-V(D)PPT-KVKVKVKV-NH2) has been shown to form nanofibrils having a cross-section of two folded peptides forming a hydrophobic, valine-rich core, and the polymerized fibril exhibits primarily β-sheet hydrogen bonding.1-7 These nanofibrils form hydrogel networks through fibril entanglements as well as fibril branching.8 Fibrillar branching in MAX1 hydrogel networks provide the ability to flow under applied shear stress and immediately reform a hydrogel solid on cessation of shear. New β-hairpins were designed to limit branching during nanofibril growth because of steric specificity in the assembled fibril hydrophobic core. The nonturn valines of MAX1 were substituted by 2-naphthylalanine (Nal) and alanine (A) residues, with much larger and smaller side chain volumes, respectively, to obtain LNK1 (Nal)K(Nal)KAKAK-V(D)PPT-KAKAK(Nal)K(Nal)-NH2. LNK1 was targeted to self-associate with a specific "lock and key" complementary packing in the hydrophobic core in order to accommodate the Nal and Ala residue side chains. The experimentally observable manifestation of reduced fibrillar branching in the LNK1 peptide is the lack of solid hydrogel formation after shear in stark contrast to the MAX1 branched fibril system. Molecular dynamics simulations provide a molecular picture of interpeptide interactions within the assembly that is consistent with the branching propensity of MAX1 vs LNK1 and in agreement with experimental observations.