Can Arsenates Replace Phosphates in Natural Biochemical
Processes? A Computational Study
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Abstract
A bacterial strain, GFAJ-1 was recently
proposed to be substituting
arsenic for phosphorus to sustain its growth. We have performed theoretical
calculations for analyzing this controversial hypothesis by examining
the addition of phosphate to ribose and glucose. Dispersion corrected
Density Functional Theory (DFT) calculations in small molecules and
QM/MM calculations on clusters derived from crystal structure are
performed on structures involved in phosphorylation, considering both
phosphates and arsenates. The exothermicity as well as the activation
barriers for phosphate and arsenate transfer were examined. Quantum
mechanical studies reveal that the relative stability of the products
decrease marginally with successive substitution of P with As. However,
simultaneously, the transition state barriers decrease with P replacement.
This indicates that, kinetically, addition of As is more facile. Pseudorotation
barriers for the pentavalent intermediates formed during the nucleophilic
attack are also analyzed. A monotonic increase in barriers is observed
for pseudorotation with the successive replacement of phosphorus with
arsenic in methyl-DHP. A glucokinase crystal structure was chosen
to construct a model system for QM/MM calculations. Free energy of
the reaction (Δ<i>G</i>) reduces by less than 2.0
kcal/mol and the activation barrier (Δ<i>G</i><sup>‡</sup>) decreases by ∼1 kcal/mol on arsenic incorporation.
Thus, both DFT and QM/MM calculations show that arsenic can readily
substitute phosphorus in key biomolecules. Secondary kinetic isotope
effects for phosphorylation mechanism obtained by QM/MM calculations
are also reported. The solvent kinetic isotopic effects (SKIE) for
ATP and ATP (As) are calculated to be 5.81 and 4.73, respectively.
A difference of ∼1.0 in SKIE suggests that it should be possible
to experimentally determine the As–phosphorylation process