Multivalent ions and biomolecules: Attempting a comprehensive perspective

Abstract

Ions are ubiquitous in nature. They play a key role for many biological processes on the molecular scale, from molecular interactions, to mechanical properties, to folding, to self‐organisation and assembly, to reaction equilibria, to signalling, to energy and material transport, to recognition etc. Going beyond monovalent ions to multivalent ions, the effects of the ions are frequently not only stronger (due to the obviously higher charge), but qualitatively different. A typical example is the process of binding of multivalent ions, such as Ca2+, to a macromolecule and the consequences of this ion binding such as compaction, collapse, potential charge inversion and precipitation of the macromolecule. Here we review these effects and phenomena induced by multivalent ions for biological (macro)molecules, from the “atomistic/molecular” local picture of (potentially specific) interactions to the more global picture of phase behaviour including, e. g., crystallisation, phase separation, oligomerisation etc. Rather than attempting an encyclopedic list of systems, we rather aim for an embracing discussion using typical case studies. We try to cover predominantly three main classes: proteins, nucleic acids, and amphiphilic molecules including interface effects. We do not cover in detail, but make some comparisons to, ion channels, colloidal systems, and synthetic polymers. While there are obvious differences in the behaviour of, and the relevance of multivalent ions for, the three main classes of systems, we also point out analogies. Our attempt of a comprehensive discussion is guided by the idea that there are not only important differences and specific phenomena with regard to the effects of multivalent ions on the main systems, but also important similarities. We hope to bridge physico‐chemical mechanisms, concepts of soft matter, and biological observations and connect the different communities further.

Albumin–Hyaluronan Interactions: Influence of Ionic Composition Probed by Molecular Dynamics

“…The difference in the effect of Ca 2+ and Mg 2+ is suggested to be due to the lower hydration of Ca 2+ . Noteworthy, charge inversion and ion-bridge formation with divalent cations has been well described in the literature [45][46][47][48][49][50][51]. However, the obtained molecular dynamics simulations are not clear in the importance of these effects for the case of Mg 2+ .…”

Temperature and salt controlled tuning of protein clusters

“…BSA solutions in the presence of various cations constitute a well-explored and robust model system in terms of its macroscopic phase behavior as well as in terms of its structure and protein-protein interactions accessible by small angle scattering. 26,27 The cations binding to the protein surface induce charge compensation and, ultimately, charge inversion for increasing concentrations c s of trivalent salts in aqueous solutions of negatively charged globular proteins, which results in complex phase diagrams (Fig. 1a).…”

“…1a). 26,27 Nevertheless, a clear understanding of the cluster formation upon approaching phase transitions is still missing.…”

Effects of Ionic Liquids on Metalloproteins

“…Examples include the structural bridging of alginate chains by Ca 2+ [ 20 ], Mg 2+ bridging and charge stabilization of the bacterial lipopolysaccharides [ 21 ], stabilization and structural modification of DNA and RNA by numerous monovalent and divalent cations [ 21 , 22 , 23 ], and metal-mediated catalysis by nucleic acids [ 24 , 25 ]. For readers interested in a comprehensive review of metal ion interactions with biomolecules, we suggest the recent reviews by Shchreiber and coworkers and/or by Bechtold and coworkers [ 26 , 27 ].…”