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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 in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis‐competent configurations in which the conserved glutamate in the Walker‐B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.