K+-Selective Compaction of Flexible Ionophore PF1022A: Conformational Landscapes of Alkali Metal Complexes

Abstract The natural cyclic octadepsipeptide ionophore PF1022A (PFA) selectively transports physiologically relevant K+ over Na+ across lipid membranes; however, its underlying structural mechanism remains unclear. Here, variable-temperature ion mobility mass spectrometry and theoretical calculations revealed the conformational landscapes of PFA-alkali metal complexes. The system exhibits a distinct ion-size dependence: smaller cations (Li+, Na+) favor bulky architectures, larger cations (K+, Rb+) induce systematic compaction, and the oversized Cs+ complex deviates from this trend via rapid conformational interconversion. Crucially, the transport-inactive Na+ complex preferentially adopts a bulky structure that exposes the cation, whereas the transport-active K+ complex forms a compact conformer effectively shielded by two benzyl side chains. This compact structure possesses a significantly reduced collision cross section and a low solvent-accessible 3D polar surface area. These findings suggest that selective ion transport by flexible ionophores is reinforced by adaptive compaction into an apolar conformation, facilitating efficient diffusion through the hydrophobic membrane’s interior.