Spontaneous formation of KCl aggregates in biomolecular simulations: A force field issue

Abstract: Realistic all-atom simulation of biological systems requires accurate modeling of both the biomolecules and their ionic environment. Recently, ion nucleation phenomena leading to the rapid growth of KCl or NaCl clusters in the vicinity of biomolecular systems have been reported. To better understand this phenomenon, molecular dynamics simulations of KCl aqueous solutions at three (1.0, 0.25, and 0.10 M) concentrations were performed. Two popular water models (TIP3P and SPC/E) and two Lennard-Jones parameter sets (AMBER and Dang) were combined to produce a total of 80 ns of molecular dynamics trajectories. Results suggest that the use of the Dang cation Lennard-Jones parameters instead of those adopted by the AMBER force-field produces a more accurate description of the ionic solution. In the later case, formation of salt aggregates is probably indicative of an artifact resulting from misbalanced force-field parameters. Because similar results were obtained with two different water parameter sets, the simulations exclude a water model dependency in the formation of anomalous ionic clusters. Overall, the results strongly suggest that for accurate modeling of ions in biomolecular systems, great care should be taken in choosing balanced ionic parameters even when using the most popular force-fields. These results invite a reexamination of older data obtained using available force-fields and a thorough check of the quality of current parameters sets by performing simulations at finite (>0.25 M) instead of minimal salt conditions