From Amorphous Bundles to Nanoporous Peptide Frameworks: Solvent-Driven Self-Assembly of Pro-Val-Pro-Val.

Peptides are ubiquitous and functionally diverse biomolecules with a strong propensity to form noncovalent nanostructures of unexpected complexity. Using nuclear magnetic resonance (NMR), X-ray diffraction, and computational modeling, we show that the amphiphilic tetrapeptide l-prolyl-l-valyl-l-prolyl-l-valine (PVPV) undergoes solvent-directed self-assembly into two molecular frameworks, each built upon a helical motif formed through charge-assisted hydrogen bonding. Water-methanol crystallization yields a solvent-stabilized porous tetragonal framework, whereas pure water produces either a low-hydration amorphous phase or a dense, disordered triclinic form. These behaviors challenge first-principles modeling and expose limitations of static semilocal density functional theory. Calculations indicate that the porous framework is energetically less favorable, highlighting the importance of water disorder and conformational flexibility in forming metastable structures. The low-hydration phase exhibits intrinsic conformational disorder, motivating an in-depth investigation via NMR crystallography. Advanced solid-state NMR on isotopically labeled samples provides assignments not achievable through conventional approaches, revealing subtle molecular distortions that modulate local ordering.