Nadine Schwierz

Reversed Anionic Hofmeister Series: The Interplay of Surface Charge and Surface Polarity

We describe a two-scale modeling approach toward anion specificity at surfaces of varying charge and polarity. Explicit-solvent atomistic molecular dynamics simulations at neutral hydrophobic (i.e., nonpolar) and neutral hydrophilic (i.e., polar) self-assembled monolayers furnish potentials of mean force for Na(+) and the halide anions F(-), Cl(-), and I(-) which are then used within Poisson-Boltzmann theory to calculate ionic distributions at surfaces of arbitrary charge for finite ion concentration. On the basis of calculated long-ranged electrostatic forces and coagulation properties, we obtain the direct anionic Hofmeister series at negatively charged hydrophobic surfaces. Reversal takes place when going to negative polar or to positive nonpolar surfaces, leading to the indirect series, while for positive polar surfaces the direct series is again obtained. This is in full accordance with a recent experimental classification of colloidal coagulation kinetics and also reflects the trends of the ion specific solubility properties of proteins. A schematic Hofmeister phase diagram is proposed. Partial series reversal is understood as a transient phenomenon for surfaces of intermediate polarity or charge.

Anionic and Cationic Hofmeister Effects on Hydrophobic and Hydrophilic Surfaces

Using a two-step modeling approach, we address the full spectrum of direct, reversed, and altered ionic sequences as the charge of the ion, the charge of the surface, and the surface polarity are varied. From solvent-explicit molecular dynamics simulations, we extract single-ion surface interaction potentials for halide and alkali ions at hydrophilic and hydrophobic surfaces. These are used within Poisson-Boltzmann theory to calculate ion density and electrostatic potential distributions at mixed polar/unpolar surfaces for varying surface charge. The resulting interfacial tension increments agree quantitatively with experimental data and capture the Hofmeister series, especially the anomaly of lithium, which is difficult to obtain using continuum theory. Phase diagrams that feature different Hofmeister series as a function of surface charge, salt concentration, and surface polarity are constructed from the long-range force between two surfaces interacting across electrolyte solutions. Large anions such as iodide have a high hydrophobic surface affinity and increase the effective charge magnitude on negatively charged unpolar surfaces. Large cations such as cesium also have a large hydrophobic surface affinity and thereby compensate an external negative charge surface charge most efficiently, which explains the well-known asymmetry between cations and anions. On the hydrophilic surface, the size-dependence of the ion surface affinity is reversed, explaining the Hofmeister series reversal when comparing hydrophobic with hydrophilic surfaces.

On the Relationship between Peptide Adsorption Resistance and Surface Contact Angle: A Combined Experimental and Simulation Single-Molecule Study

The force-induced desorption of single peptide chains from mixed OH/CH(3)-terminated self-assembled monolayers is studied in closely matched molecular dynamics simulations and atomic force microscopy experiments with the goal to gain microscopic understanding of the transition between peptide adsorption and adsorption resistance as the surface contact angle is varied. In both simulations and experiments, the surfaces become adsorption resistant against hydrophilic as well as hydrophobic peptides when their contact angle decreases below θ ≈ 50°-60°, thus confirming the so-called Berg limit established in the context of protein and cell adsorption. Entropy/enthalpy decomposition of the simulation results reveals that the key discriminator between the adsorption of different residues on a hydrophobic monolayer is of entropic nature and thus is suggested to be linked to the hydrophobic effect. By pushing a polyalanine peptide onto a polar surface, simulations reveal that the peptide adsorption resistance is caused by the strongly bound water hydration layer and characterized by the simultaneous gain of both total entropy in the system and total number of hydrogen bonds between water, peptide, and surface. This mechanistic insight into peptide adsorption resistance might help to refine design principles for anti-fouling surfaces.

Specific ion binding to carboxylic surface groups and the pH dependence of the Hofmeister series.

Ion binding to acidic groups is a central mechanism for ion-specificity of macromolecules and surfaces. Depending on pH, acidic groups are either protonated or deprotonated and thus change not only charge but also chemical structure with crucial implications for their interaction with ions. In a two-step modeling approach, we first determine single-ion surface interaction potentials for a few selected halide and alkali ions at uncharged carboxyl (COOH) and charged carboxylate (COO(-)) surface groups from atomistic MD simulations with explicit water. Care is taken to subtract the bare Coulomb contribution due to the net charge of the carboxylate group and thereby to extract the nonelectrostatic ion-surface potential. Even at this stage, pronounced ion-specific effects are observed and the ion surface affinity strongly depends on whether the carboxyl group is protonated or not. In the second step, the ion surface interaction potentials are used in a Poisson-Boltzmann model to calculate the surface charge and the potential distribution in the solution depending on salt type, salt concentration, and solution pH in a self-consistent manner. Hofmeister phase diagrams are derived on the basis of the long-ranged forces between two carboxyl-functionalized surfaces. For cations we predict direct, reversed, and altered Hofmeister series as a function of the pH, qualitatively similar to recent experimental results for silica surfaces. The Hofmeister series reversal for cations is rationalized by a reversal of the single-cation affinity to the carboxyl group depending on its protonation state: the deprotonated carboxylate (COO(-)) surface group interacts most favorably with small cations such as Li(+) and Na(+), whereas the protonated carboxyl (COOH) surface group interacts most favorably with large cations such as Cs(+) and thus acts similarly to a hydrophobic surface group. Our results provide a general mechanism for the pH-dependent reversal of the Hofmeister series due to the different specific ion binding to protonated and deprotonated surface groups.

Dynamics of Seeded Aβ40-Fibril Growth from Atomistic Molecular Dynamics Simulations: Kinetic Trapping and Reduced Water Mobility in the Locking Step

Filamentous β-amyloid aggregates are crucial for the pathology of Alzheimers disease. Despite the tremendous biomedical importance, the molecular pathway of growth propagation is not completely understood and remains challenging to investigate by simulations due to the long time scales involved. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to obtain free energy profiles and kinetic information from position-dependent diffusion profiles for three different Aβ9-40-growth processes: fibril elongation by single monomers at the structurally unequal filament tips and association of larger filament fragments. Our approach provides insight into the molecular steps of the kinetic pathway and allows close agreement with experimental binding free energies and macroscopic growth rates. Water plays a decisive role, and solvent entropy is identified as the main driving force for assembly. Fibril growth is disfavored energetically due to cancellation of direct peptide-peptide interactions and solvation effects. The kinetics of growth is consistent with the characteristic dock/lock mechanism, and docking is at least 2 orders of magnitude faster. During initial docking, interactions are mediated by transient non-native hydrogen bonds, which efficiently catch the incoming monomer or fragment already at separations of about 3 nm. In subsequent locking, the dynamics is much slower due to formation of kinetically trapped conformations caused by long-lived non-native hydrogen bonds. Fibril growth additionally requires collective motion of water molecules to create a dry binding interface. Fibril growth is further retarded due to reduced mobility of the involved hydration water, evident from a 2-fold reduction of the diffusion coefficient.

Non-monotonic crossover from single-file to regular diffusion in micro-channels

The diffusion behavior of interacting particles determines the behavior of a large number of systems ranging from pedestrians crossing a road to ions passing through channels in living cells. Here we present a system in which the nature of the diffusion process varies with changes in the external conditions. We find this special behavior in a colloidal model system, consisting of micron sized particles which are confined to narrow channels and interact via induced magnetic dipoles. When the density of these particles is changed, diffusion alternates between normal Fickian behavior and single-file diffusion. This anomalous behavior is induced by the order of the particles in the restricted geometry and does not depend on the exact nature of the inter-particle interactions.

Effective Interaction between Two Ion-Adsorbing Plates: Hofmeister Series and Salting-In/Salting-Out Phase Diagrams from a Global Mean-Field Analysis

Interactions between ions and solutes are key to ion-specificity. A generic model in which ions interact via square well potentials of finite range with charged plates is solved analytically on the Poisson-Boltzmann level and analyzed globally for varying surface charge, salt concentration, and ion-surface affinity. Ion adsorption as well as depletion can lead to stably bound plates at finite separation, relevant for the equilibrium salting-out of small solutes such as proteins. The interplate pressure at large plate separation, relevant for aggregation kinetics of large solutes, exhibits direct as well as indirect Hofmeister ordering, depending on surface charge and salt concentration. A simple method for mapping explicit ion-surface potentials of mean force as obtained from solvent-explicit molecular dynamics simulations onto square-well potential parameters is demonstrated.

The Effect of Temperature on Single-Polypeptide Adsorption

The hydrophobic attraction (HA) is believed to be one of the main driving forces for protein folding. Understanding its temperature dependence promises a deeper understanding of protein folding. Herein, we present an approach to investigate the HA with a combined experimental and simulation approach, which is complementary to previous studies on the temperature dependence of the solvation of small hydrophobic spherical particles. We determine the temperature dependence of the free-energy change and detachment length upon desorption of single polypeptides from hydrophobic substrates in aqueous environment. Both the atomic force microscopy (AFM) based experiments and the molecular dynamics (MD) simulations show only a weak dependence of the free energy change on temperature. In fact, depending on the substrate, we find a maximum or a minimum in the temperature-dependent free energy change, meaning that the entropy increases or decreases with temperature for different substrates. These observations are in contrast to the solvation of small hydrophobic particles and can be rationalized by a compensation mechanism between the various contributions to the desorption force. On the one hand this is reminiscent of the protein folding process, where large entropic and enthalpic contributions compensate each other to result in a small free energy difference between the folded and unfolded state. On the other hand, the protein folding process shows much stronger temperature dependence, pointing to a fundamental difference between protein folding and adsorption. Nevertheless such temperature dependent single molecule desorption studies open large possibilities to study equilibrium and non-equilibrium processes dominated by the hydrophobic attraction.

Effects of confinement and external fields on structure and transport in colloidal dispersions in reduced dimensionality

In this work, we focus on low-dimensional colloidal model systems, via simulation studies and also some complementary experiments, in order to elucidate the interplay between phase behavior, geometric structures and transport properties. In particular, we try to investigate the (nonlinear!) response of these very soft colloidal systems to various perturbations: uniform and uniaxial pressure, laser fields, shear due to moving boundaries and randomly quenched disorder. We study ordering phenomena on surfaces or in monolayers by Monte Carlo computer simulations of binary hard-disk mixtures, the influence of a substrate being modeled by an external potential. Weak external fields allow a controlled tuning of the miscibility of the mixture. We discuss the laser induced de-mixing for the three different possible couplings to the external potential. The structural behavior of hard spheres interacting with repulsive screened Coulomb or dipolar interaction in 2D and 3D narrow constrictions is investigated using Brownian dynamics simulations. Due to misfits between multiples of the lattice parameter and the channel widths, a variety of ordered and disordered lattice structures have been observed. The resulting local lattice structures and defect probabilities are studied for various cross sections. The influence of a self-organized order within the system is reflected in the velocity of the particles and their diffusive behavior. Additionally, in an experimental system of dipolar colloidal particles confined by gravity on a solid substrate we investigate the effect of pinning on the dynamics of a two-dimensional colloidal liquid. This work contains sections reviewing previous work by the authors as well as new, unpublished results. Among the latter are detailed studies of the phase boundaries of the de-mixing regime in binary systems in external light fields, configurations for shear induced effects at structured walls, studies on the effect of confinement on the structures and defect densities in three-dimensional systems, the effect of confinement and barriers on two-dimensional flow and diffusion, and the effect of pinning sites on the diffusion.

From Aβ Filament to Fibril: Molecular Mechanism of Surface-Activated Secondary Nucleation from All-Atom MD Simulations

Secondary nucleation pathways in which existing amyloid fibrils catalyze the formation of new aggregates and neurotoxic oligomers are of immediate importance for the onset and progression of Alzheimers disease. Here, we apply extensive all-atom molecular dynamics simulations in explicit water to study surface-activated secondary nucleation pathways at the extended lateral β-sheet surface of a preformed Aβ9-40 filament. Calculation of free-energy profiles allows us to determine binding free energies and conformational intermediates for nucleation complexes consisting of 1-4 Aβ peptides. In addition, we combine the free-energy profiles with position-dependent diffusion profiles to extract complementary kinetic information and macroscopic growth rates. Single monomers bind to the β-sheet surface in a disordered, hydrophobically collapsed conformation, whereas dimers and larger oligomers can retain a cross-β conformation resembling a more ordered fibril structure. The association processes during secondary nucleation follow a dock/lock mechanism consisting of a fast initial encounter phase (docking) and a slow structural rearrangement phase (locking). The major driving forces for surface-activated secondary nucleation are the release of a large number of hydration water molecules and the formation of hydrophobic interface contacts, the latter being in contrast to the elongation process at filament tips, which is dominated by the formation of stable and highly specific interface hydrogen bonds. The calculated binding free energies and the association rates for the attachment of Aβ monomers and oligomers to the extended lateral β-sheet surface of the filament seed are higher compared to those for elongation at the filament tips, indicating that secondary nucleation pathways can become important once a critical concentration of filaments has formed.