Probing the Conformational Preference to β-Strand during Peptide Self-Assembly

Alanine-rich tetrapeptides like A3K dominantly exist as polyproline II helices in dilute aqueous solutions. However, during self-assembly, based on the free energy calculation in implicit solvent for various peptide conformations, only the peptides in the β-strand conformation can be packed closely. This necessitates the conformational transition to the β-strand commonly observed during peptide self-assembly such as in amyloid fibril formation. In fact, the closest interpeptide distance of 4.8 Å is consistent with the interstrand distance determined from the X-ray diffraction pattern of many amyloid fibrils. The position of free energy minimum obtained from implicit solvent calculation matches exactly with the explicit solvent simulation through umbrella sampling when the peptide conformations are restrained, demonstrating the applicability of the former for rapid screening of peptide configurations favorable for self-assembly. The barrier in the free energy profile in the presence of water arises out of the entropic restriction on the interstitial water molecules while satisfying the hydrogen bonding of both the peptides by forming water mediated hydrogen bond bridge. Further, the high energy barrier observed for the β-strand suggests that peptides initially tend to self-assemble in the polyproline II structure to mitigate the desolvation energy cost; the transition to the β-strand would happen only in the later stage after crossing the barrier. The umbrella sampling simulations with peptides allowed to change conformations, relative to each other, confirm the dynamic conformational transition during the course of the self-assembly supporting the "dock and lock" mechanism suggested for amyloid fibrillar growth.