ATP–Magnesium Coordination: Protein Structure-Based Force Field Evaluation and Corrections

[Image: see text] In the numerous molecular recognition and catalytic processes across biochemistry involving adenosine triphosphate (ATP), the common bioactive form is its magnesium chelate, ATP·Mg(2+). In aqueous solution, two chelation geometries predominate, distinguished by bidentate and tridentate Mg(2+)–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·Mg(2+) 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·Mg(2+)–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·Mg(2+) 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·Mg(2+) 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.