Whether proton transition to the triphosphate tail of ATP occurs at protein kinase environment: A Car‐Parrinello ab initio molecular dynamics study

Protonation state of the triphosphate tail of ATP (adenosine triphosphate) in protein environment is a fundamental issue, which has significant impact on the mechanism investigation of biochemical processes with ATP involved. Proton transition from surroundings (water molecule coordinating to magnesium, H_W; amino group of Lys, H_L) to the ATP tail in the catalytic core of protein kinase found recently disproved the commonly accepted deprotonation state of ATP tail. In this account, Car‐Parrinello ab initio molecular dynamics (CP‐AIMD) method has been employed to examine whether the proton transition occurs. To provide a comparison basis for the dynamics simulations, static quantum mechanics (QM), and combined quantum mechanics and molecular mechanics (QM/MM) calculations have also been carried out. Consistent results have been obtained that complete transition of hydrogen from the surroundings to the triphosphate tail of ATP is not allowed. The most dominant conformations correspond to the ones with H_W bonding to O(W) and H‐bonding to O(ATP), O(W)‐H_W···O(ATP)], H_L bonding to N(Lys) and H‐bonding to O(ATP), N(Lys)‐H_L···O(ATP)]. Metastable structures with one hydrogen atom bonding with two heavy atoms (hydrogen acceptors) were also located by our dynamic simulations. This bonding mode can satisfy the hungering for hydrogen of the two heavy atoms simultaneously. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008