Abstract
Within the homologous series of amphiphilic peptides AnK, both A8K and A10K self-assemble in water to form twisted ribbon fibrils with lengths around 100 nm. The structure of the fibrils can be described in terms of twisted β-sheets extending in the direction of the fibrils, laminated to give a constant cross section of 4 nm by 8 nm. The finite width of the twisted ribbons can be reasonably explained within a simple thermodynamic model, considering a free energy penalty for the stretching of hydrogen bonds along the twisted β-sheets and an interfacial free energy gain for the lamination of the hydrophobic β-sheets. In this study, we characterize the self-assembly behavior of these peptides in nonaqueous solutions as a route to probe the role of hydrophobic interaction in fibril stabilization. Both peptides, in methanol and N,N-dimethylformamide, were found to form fibrillar aggregates with the same β-sheet structure as in water but with slightly smaller cross-sectional sizes. However, the gel-like texture, the slow relaxation in dynamic light scattering experiments, and a correlation peak in the small-angle X-ray scattering pattern highlighted enhanced interfibril interactions in the nonaqueous solvents in the same concentration range. This could be ascribed to a higher effective volume of the aggregates because of enhanced fibril growth and length, as suggested by light scattering and cryogenic transmission electron microscopy analyses. These effects can be discussed considering how the solvent properties affect the different energetic contributions (hydrophobic, electrostatic, and hydrogen bonding) to fibril formation. In the analyzed case, the decreased hydrogen bonding propensity of the nonaqueous solvents makes the hydrogen bond formation along the fibril a key driving force for peptide assembly, whereas it represents a nonrelevant contribution in water.
Highlights
Understanding the driving forces for peptide self-assembly is of both fundamental and practical significance
We considered the self-assembly of the peptides in two nonaqueous solvents: methanol (MeOH), which can be considered the first more hydrophobic analogue of water in which one hydrogen atom is replaced by a methyl group, and N,N-dimethylformamide (DMF), a solvent commonly used in peptide synthesis and considered to be “aprotic” because it is only a hydrogen bond acceptor
The less favorable hydrogen bonding between the peptide and solvent molecules in MeOH and DMF compared to water could have an impact on the kinetics of fibril growth
Summary
Understanding the driving forces for peptide self-assembly is of both fundamental and practical significance These aggregation processes are relevant in the formation of protein- and peptidebased amyloid fibrils involved in both diseases and functional aspects of biological systems.[1,2] Peptide self-assembly represents a versatile tool for building structural elements made of designed peptide building blocks for advanced biomaterial applications.[3−5] In addition, for a growing field such as peptide-based therapeutics, knowing the phase behavior and stability of various peptide solutions and formulations is of outmost importance.[6] Because of the multifaceted chemical nature of the natural amino acids composing the peptide building blocks, their self-assembly is dictated by various noncovalent interactions (hydrophobic effect, hydrogen bonding, electrostatic interactions, and π−π stacking) and their interplay.[7] Their relative importance will depend on the peptide sequence as well as the properties of the surroundings, determining a complex free energy landscape with deep valleys corresponding to low free energy states. The self-assembly has been suggested to occur through crystallization with the processes of nucleation
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