Structural and dynamic insights on the EmrE protein with TPP and related substrates through molecular dynamics simulations.

EmrE is a bacterial transporter protein that forms an anti-parallel homodimer with four transmembrane helices in each monomer. EmrE transports positively charged aromatic compounds, such as TPP and its derivatives. We performed molecular dynamics (MD) simulations of EmrE in complex with TPP, MeTPP, and MBTPP embedded in a membrane. The detailed molecular properties and interactions were analysed for all EmrE-ligand complexes. Our MD results identified that Lys22, Tyr40, Phe44, Trp45, and Trp63 formed potential π interactions with all three ligands and further confirmed the essential role of Glu14. Moreover, distance analysis and structural changes in the EmrE translocation pathway suggest that ligand recognition and protein conformational changes depend on the structural properties of the substrate. Analysis of the movement of the ligand in the protein binding site and rotation of the ligand's aromatic rings confirm that substrates with aromatic moieties, such as MBTPP, exhibit relatively stable binding to EmrE. Interestingly, the aromatic rings of Tyr40, Phe44, Trp45, and Trp63 underwent parallel movements with the aromatic rings of TPP. Based on the MD results, we propose that π interactions, as well as the mutual rotation of the aromatic rings in the protein and ligand, can be regarded as sources of ligand movement, and thus, the whole complex may work as a "molecular propeller".