Can Arsenates Replace Phosphates in Natural Biochemical Processes? A Computational Study

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 (ΔG) reduces by less than 2.0 kcal/mol and the activation barrier (ΔG(‡)) 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.

Effect of arsenate substitution on phosphate repository of cell: a computational study

“…[9]. Physiologically, these are dianionic monoesters of P i and highly sensitive to As i substitution [10]. Hence, to investigate the effect of As i substitution on the P i repository of the cell a comparative study at different biomolecular level is needed, that is not merely confined to analysing the impact of As i substitution on the stability of a particular P i biomolecule.…”

The excited-state proton transfer mechanism in water-bridged 4-hydroxybenzoate: spectroscopy and DFT/TDDFT studies

“…the transfer energy barrier of the two different clusters proves that both two ESPT pathways are feasible and the later is more reasonable than the former one. According to the principle presented in literature by Datta, 35,36 isotope atoms will lead to various transition state energies, which nally results in different PT reaction rates. Therefore, it is possible to distinguish 4-HB$(H 2 O) 5 and 4-HB$(H 2 O) 3 by solvent kinetic isotope effects.…”

Investigation of kinetics of phenyl radicals with ethyl formate in the gas phase using cavity ring-down spectroscopy and theoretical methodologies

“…For the visualization of the optimized geometries and normal modes of all the stationary points, Gauss-View 6.0 [23] was used. To ensure that the obtained TSs connect both the reactants and products along the minimum energy pathway (MEP), intrinsic reaction coordinate (IRC) calculations [24,25] were executed at B3LYP/6-31 + G(d,p) level of theory and are depicted in the supplementary information (SI). The IRC calculations also ensured that all the obtained TSs follow distinct MEPs.…”