ATP (adenosine triphosphate) is the energy currency of life. The energy that comes from ATP is utilized by numerous proteins, including members of the ATP binding cassette (ABC) transporter family, which move various substrates across cellular membranes. ABC transporters are involved in several essential physiological functions and can be found anywhere from bacteria to humans. A prominent example of ABC transporters is ABCB1/P-glycoprotein, which protects multidrug resistant cancer cells by removing chemotherapeutic agents from the cells. Intriguingly, the mechanism by which ABC transporters harness the energy stored in the ATP molecule remains ill defined. In particular, how energy is converted into protein motion remains largely unknown. Using in silico simulations, we were able to get an insight to the mechanisms by which ATP promotes molecular movements leading to conformational changes and ultimately to substrate transport by ABCB1.
The cover image for the January 23 issue of the Biophysical Journal shows the electrostatic fields produced by the dimer of the nucleotide binding domains (NBD) of ABCB1. The image depicts the delicate architecture of the protein matching the ATP molecule (shown as orange sticks) and highlights the multiple levels of interactions ensuring efficient protein dimerization, which eventually induces protein motions. Blue and orange fields represent areas of positive and negative potentials, which are complemented by the oppositely charged phosphates of ATP and the indispensable Mg2+ cofactor (green sphere), respectively. In contrast, the green field shows a hydrophobic surface that is predisposed for binding the adenine base of ATP. Motifs conserved among ATPase active proteins and responsible for generating these fields are highlighted by colored cartoon and stick representation (A-loop – pink; X-loop – gray; Walker A – red; Signature motif – magenta; Walker B – orange; Q-loop – dark green).
For a long time proteins were understood in the frame of the “structure equals function” paradigm. Protein dynamics is getting increasing attention when addressing questions of protein function. Importantly, protein function frequently includes motions, which in turn requires energy input. For membrane transporters, the working mechanisms can only be fully grasped through the understanding of energy input. While we are not suggesting that all ABC transporters would follow the energy harnessing mechanism described in our work, we believe that our atomistic insight can provide important information about the function of primary active proteins.
– Dániel Szöllősi, Gergely Szakács, Peter Chiba, Thomas Stockner