Multiscale QM/MM Simulations of ATP Hydrolysis Mechanism in ABC-Transporters

Abstract

Adenosine triphosphate (ATP) binding cassette (ABC) transporters are ubiquitous molecular motor proteins that translocate various substrates across cell membranes at the expense of ATP hydrolysis. Although it is known that nucleotide binding domains in ABC-transporters contain a collection of characteristic sequence motifs, the precise mechanism under which ATP is hydrolyzed in these systems remains unknown. By using multiscale combined quantum mechanical and molecular mechanical (QM/MM) free energy simulations, we examined several possible ATP hydrolysis mechanisms in members of ABC-transporters. Our results reveal how the active site residues may participate in the catalytic mechanism and how protein dynamics may contribute to catalysis.