Cation–π Interactions Greatly Influence Ion Transportability of the Light-Driven Sodium Pump KR2: A Molecular Dynamics Study

Krokinobacter eikastus rhodopsin
2 (KR2) is a typical light-driven sodium pump. Although wild-type
KR2 exhibits high Na+ selectivity, mutagenesis performed
on the residues constituting the entrance enables permeation of K+ and Cs+, while the underlying mechanism remains
elusive. This study presents a comprehensive molecular dynamics investigation,
including force field optimization, metadynamics, and alchemical free
energy methods, to explore the N61L/G263F mutant of KR2, which exhibits
transportability for K+ and Cs+. The introduced
Phe263 residue can directly promote ion binding at the entrance through
cation–π interactions, while the N61L mutation can enhance
ion binding at Phe46 by relieving steric hindrance. These results
suggest that cation–π interactions may significantly
influence the ion transportability and selectivity of KR2, which can
provide important insights for protein engineering and the design
of artificial ion transporters.