Hexahydrated Mg2+ Binding and Outer-Shell Dehydration on RNA Surface.

The interaction between metal ions, especially Mg2+ ions, and RNA plays a critical role in RNA folding. Upon binding to RNA, a metal ion that is fully hydrated in bulk solvent can become dehydrated. Here we use molecular dynamics simulation to investigate the dehydration of bound hexahydrated Mg2+ ions. We find that a hydrated Mg2+ ion in the RNA groove region can involve significant dehydration in the outer hydration shell. The first or innermost hydration shell of the Mg2+ ion, however, is retained during the simulation because of the strong ion-water electrostatic attraction. As a result, water-mediated hydrogen bonding remains an important form for Mg2+-RNA interaction. Analysis for ions at different binding sites shows that the most pronounced water deficiency relative to the fully hydrated state occurs at a radial distance of around 11 Å from the center of the ion. Based on the independent 200 ns molecular dynamics simulations for three different RNA structures (Protein Data Bank: 1TRA, 2TPK, and 437D), we find that Mg2+ ions overwhelmingly dominate over monovalent ions such as Na+ and K+ in ion-RNA binding. Furthermore, application of the free energy perturbation method leads to a quantitative relationship between the Mg2+ dehydration free energy and the local structural environment. We find that ΔΔGhyd, the change of the Mg2+ hydration free energy upon binding to RNA, varies linearly with the inverse distance between the Mg2+ ion and the nearby nonbridging oxygen atoms of the phosphate groups, and ΔΔGhyd can reach -2.0 kcal/mol and -3.0 kcal/mol for an Mg2+ ion bound to the surface and to the groove interior, respectively. In addition, the computation results in an analytical formula for the hydration ratio as a function of the average inverse Mg2+-O distance. The results here might be useful for further quantitative investigations of ion-RNA interactions in RNA folding.