<p>We report a mechanism of adenosine triphosphate (ATP)
to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V
adenylyl cyclase revealed in molecular dynamics (MD) and quantum
mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of
computationally derived enzyme-substrate (ES) structures showing an important role
of coordination shells of magnesium ions in the solvent accessible active site.
Several stable six-fold coordination shells of Mg<sub>A</sub><sup>2+ </sup>are observed
in MD simulations of ES complexes. In the lowest energy ES conformation, the
coordination shell of Mg<sub>A</sub><sup>2+ </sup>does not include the O<sub>δ1</sub>
atom of the conserved Asp440 residue. Starting from this conformation, a
one-step reaction mechanism is characterized which includes proton transfer
from the ribose O<sup>3'</sup>H<sup>3' </sup>group in ATP to Asp440 via a
shuttling water molecule and P<sup>A</sup>-O<sup>3A</sup> bond cleavage and O<sup>3'</sup>-P<sup>A</sup>
bond formation. The energy profile of
this route is consistent with the observed reaction kinetics. In a higher
energy ES conformation, Mg<sub>A</sub><sup>2+</sup> is bound to the O<sub>δ1</sub>(Asp440)
atom as suggested in the relevant crystal structure of the protein with a
substrate analog. The computed energy profile initiated by this ES is
characterized by higher energy expenses to complete the reaction. Consistently
with experimental data, we show that the Asp440Ala mutant of the enzyme should
exhibit a reduced but retained activity. All considered reaction pathways
include proton wires from the O<sup>3'</sup>H<sup>3' </sup>group via shuttling
water molecules. </p>
Enhancing tracer diffusivity by tuning interparticle interactions and coordination shell structure