DEHG2020-ET
P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological
importance.
Pgp nucleotide binding domains (NBDs) drive the transport cycle
through ATP binding and hydrolysis. We use molecular dynamics
simulations
to investigate the ATP hydrolysis-induced conformational
changes of NBDs. Five systems, including all possible
ATP/ADP combinations in the NBDs and the APO system are
simulated.
ATP/ADP exchange
induces NBDs conformational changes mostly within the
conserved signature motif, resulting in relative orientational
changes of the NBDs.
Nucleotide removal leads to additional
orientational changes in the NBDs, allowing their dissociation.
Furthermore, we capture putative
hydrolysis-competent configurations where the conserved
glutamate in the Walker-B motif acts as
a catalytic base capturing a water molecule likely initiating ATP
hydrolysis.