Abstract
In the numerous molecular recognition and catalytic processes across biochemistry involving adenosine triphosphate (ATP), the common bioactive form is its magnesium chelate, ATP·Mg2+. In aqueous solution, two chelation geometries predominate, distinguished by bidentate and tridentate Mg2+–phosphate coordination. These are approximately isoenergetic but separated by a high energy barrier. Force field-based atomistic simulation studies of this complex require an accurate representation of its structure and energetics. Here we focused on the energetics of ATP·Mg2+ coordination. Applying an enhanced sampling scheme to circumvent prohibitively slow sampling of transitions between coordination modes, we observed striking contradictions between Amber and CHARMM force field descriptions, most prominently in opposing predictions of the favored coordination mode. Through further configurational free energy calculations, conducted against a diverse set of ATP·Mg2+–protein complex structures to supplement otherwise limited experimental data, we quantified systematic biases for each force field. The force field calculations were strongly predictive of experimentally observed coordination modes, enabling additive corrections to the coordination free energy that deliver close agreement with experiment. We reassessed the applicability of the thus corrected force field descriptions of ATP·Mg2+ for biomolecular simulation and observed that, while the CHARMM parameters display an erroneous preference for overextended triphosphate configurations that will affect many common biomolecular simulation applications involving ATP, the force field energy landscapes broadly agree with experimental measurements of solution geometry and the distribution of ATP·Mg2+ structures found in the Protein Data Bank. Our force field evaluation and correction approach, based on maximizing consistency with the large and heterogeneous collection of structural information encoded in the PDB, should be broadly applicable to many other systems.
Highlights
Hydrolysis of adenosine triphosphate (ATP) serves as a source of chemical energy across all domains of life, driving essentially all energy-consuming cellular processes
CHARMM and Amber each predicted substantial preferences in opposite directions, with neither reproducing the experimental finding that these configurations are close to isoenergetic in solution. Addressing this discrepancy, we compared simulated solution free energy landscapes to the distribution of ATP· Mg2+ configurations found among biomolecular complexes in the Protein Data Bank (PDB)
Configurational free energy calculations for 30 structurally diverse ATP−protein complexes served to quantify systematic force field biases that led to mispredictions of the PDB coordination mode and enabled corrections to the relative free energy of the C2 and C3 coordination modes for each force field
Summary
Hydrolysis of adenosine triphosphate (ATP) serves as a source of chemical energy across all domains of life, driving essentially all energy-consuming cellular processes Both unbound in cellular surroundings and as enzyme substrates, nucleotide triphosphates occur predominantly with divalent cations, most commonly Mg2+,1,2 coordinated with the negatively charged triphosphate moiety. Nuclear magnetic resonance,[3,5] as well as infrared and Raman spectroscopy,[4] detected both C2 and C3 coordination, with tentative support for an excess of C2, suggesting a small free energy difference of at most a few kBT between C2 and C3 in solution Both configurations are biochemically relevant, and the Protein Data Bank (PDB) contains many complexes in both
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