  Adenosine triphosphate (ATP)-binding cassette (ABC) transporters form a
family of molecular motor proteins that couple ATP hydrolysis to substrate
translocation across cell membranes. Each nucleotide binding domain of
ABC-transporters contains a highly conserved H-loop Histidine residue, whose
precise mechanistic role to motor functions has remained elusive. By using
combined quantum mechanical and molecular mechanical calculations, we showed
that the conserved H-loop residue H662 in E. coli HlyB, a bacterial ABC
transporter, can act first as a general acid and then as a general base to
facilitate proton transfers in ATP hydrolysis. Without the assistance of H662,
direct proton transfer from the lytic water to ATP results in a greatly
elevated barrier height. Our findings suggest that the essential function of
the H-loop residue H662 is to provide a "chemical linchpin" that shuttles
protons between reactants through a relay mechanism, thereby catalyzing ATP
hydrolysis in HlyB.
