Interactions between cyclic nucleotides and common cations: an ab initio molecular dynamics study

We present the first{,} to the best of our knowledge{,} ab initio molecular dynamics (AIMD) investigation on three aqueous solutions where an abasic cyclic nucleotide model is solvated in the presence of distinct cations (i.e.{,} Na+{,} K+ and Mg2+). We elucidate the typical modalities of interaction between those ionic species and the nucleotide moiety by first-principles numerical simulations{,} starting from an inner-shell binding configuration on a time scale of 100 ps (total simulation time of ∼600 ps). Whereas the strong “structure-maker” Mg2+ is permanently bound to one of the two oxygen atoms of the phosphate group of the nucleotide model{,} Na+ and K+ show binding times τb of 65 ps and 10–15 ps{,} respectively{,} thus reflecting their chemical nature in aqueous solutions. Furthermore{,} we qualitatively relate these findings to approximate free-energy barriers of the cations{'} unbinding obtained by means of exploratory well-tempered metadynamics. With the aim of shedding light on the features of commonly employed force-fields (FFs){,} classical MD simulations (almost 200 trajectories with a total simulation time of ∼18 μs) using the biomolecular AMBER FF are also reported. By choosing several combinations of the parametrization for the water environment (i.e.{,} TIP3P{,} SPC/E and OPC) and cations (i.e.{,} Joung–Cheatham{,} Li–Merz 12-6 and Li–Merz 12-6-4){,} we found significant differences in the radial distribution functions and residence times compared to the ab initio results. The Na+ and K+ ions wrongly show quasi-identical radial distribution functions and the Li & Merz 12-6-4 Lennard-Jones parameters for Mg2+ were found to be essential in quickly reaching the binding state consistent with AIMD.