From Conformational Lability to Conformational Control in Short-Peptide Crystals

Abstract

Short peptides occupy a distinctive position between proteins and traditional small molecules. They combine the functional richness typical of biomolecules with the synthetic accessibility and crystallographic tractability characteristic of small-molecule systems. Their favourable physicochemical properties and exceptional structural diversity make them difficult to replicate with other classes of molecular building blocks, while enabling systematic exploration of sequence–structure relationships in crystalline materials. At the same time, short-peptide crystals are often regarded as conformationally labile, a feature that has traditionally been viewed as an obstacle to predictive peptide crystal engineering. Recent studies, however, suggest that conformational flexibility in short peptides can shift from being treated as a crystallographic complication to being explored as a potentially controllable structural variable. A key challenge is distinguishing genuine crystal-state conformational control from apparent structural changes arising from crystallisation pathways, phase conversion or recrystallisation. In this Highlight we propose a practical framework for identifying when conformational lability translates into experimentally demonstrable conformational control in peptide crystals. We discuss representative model systems, outline experimental strategies required to distinguish crystal-state conformational selection from pathway-dependent effects, and highlight emerging cases in which controlled peptide conformation influences structural organisation and functional behaviour in molecular materials.