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.

Keywords: biomolecules; biophysical chemistry; charge-mediated interactions; multivalent ions; phase behaviour.

Figure 1

Stern model combining the rigid (Helmholtz) and diffuse (Gouy‐Chapman) double layer models. The grey shaded area represents a surface immersed into bulk liquid (blue continuum). The red circles on the shaded area represent negatively charged particles, the green circles illustrate positively charged ones. The potential ψ decays linearly between the surface (ψ_S) and the outer Helmholtz layer (ψ _o.H. at a distance d_H). At d_H, the diffuse double‐layer begins and ψ decays exponentially, asymptotically approaching a value ψ_A at long distances from the charged surface. The thickness of the diffuse double‐layer corresponds to the Debye screening length (eqn. 1). Figure reproduced and adapted from Refs. [38] and [39].

Figure 2

DLVO potential for varying salt concentration c_s. With increasing c_s, the potential changes from repulsive to attractive. The aggregation barrier reflects the charge stabilisation behaviour that becomes weaker due to charge screening.

Figure 3

Part of the Hofmeister series for anions and cations. Ions on the left hand side of the series destabilise solutions and “salt out” solutes, whereas ions on the right stabilise (“salt in”) solutions.

Figure 4

Binding sites of multivalent ions in proteins (see text for details). The image illustrates the pivotal roles of negatively charged amino acid residues in coordinating the respective ions. As opposed to the Y³⁺ cations bound by BLG (b) and the Ca²⁺ ions bound by calbindin (c), binding of Fe³⁺ requires carbonate ions in addition to the protein residues coordinating the ion (seen on the right side of the orange sphere representing Fe³⁺ in (a)). The structures were visualised using UCSF Chimera164 based on PDB IDs 1SUV, 3PH5 and 6FIE.

Figure 5

Phase diagram showing regimes I, II and III, reentrant condensation and LLPS. See text for details.

Figure 6

Schematic of DNA‐ion correlations at different ion concentrations. (a): Cation binding to minor and major grooves (inspired by Refs. [347] and [348]). (b) Condensation and charge inversion of DNA molecules induced by ion‐ion‐correlation. The circles on the DNA molecules indicate the net charge of the latter (red: net negative; turquoise: net neutral; green: net positive). Figure was rendered using UCSF chimera164 and Avogadro.349

Figure 7

Schematic representation of the arrangement of cations in the bulk solution and near a monolayer of amphiphilic molecules. Image inspired by Ref. [387].