Mikael Lund

Specific ion binding to nonpolar surface patches of proteins

Employing detailed atomistic modeling we study the mechanisms behind ion binding to proteins and other biomolecules and conclude that (1) small, hard ions bind via direct ion pairing to charged surface groups and (2) large, soft ions bind to nonpolar groups via a solvent assisted attraction. Our predictions are in qualitative agreement with bulk solution data and may provide an important clue for the basic understanding of ion-specific effects in biological systems.

FAUNUS: An object oriented framework for molecular simulation

BackgroundWe present a C++ class library for Monte Carlo simulation of molecular systems, including proteins in solution. The design is generic and highly modular, enabling multiple developers to easily implement additional features. The statistical mechanical methods are documented by extensive use of code comments that – subsequently – are collected to automatically build a web-based manual.ResultsWe show how an object oriented design can be used to create an intuitively appealing coding framework for molecular simulation. This is exemplified in a minimalistic C++ program that can calculate protein protonation states. We further discuss performance issues related to high level coding abstraction.ConclusionC++ and the Standard Template Library (STL) provide a high-performance platform for generic molecular modeling. Automatic generation of code documentation from inline comments has proven particularly useful in that no separate manual needs to be maintained.

Specific Ion Binding to Macromolecules: Effects of Hydrophobicity and Ion Pairing

Using molecular dynamics simulations in an explicit aqueous solvent, we examine the binding of fluoride versus iodide to a spherical macromolecule with both hydrophobic and positively charged patches. Rationalizing our observations, we divide the ion association interaction into two mechanisms: (1) poorly solvated iodide ions are attracted to hydrophobic surface patches, while (2) the strongly solvated fluoride and to a minor extent also iodide bind via cation-anion interactions. Quantitatively, the binding affinities vary significantly with the accessibility of the charged groups as well as the surface potential; therefore, we expect the ion-macromolecule association to be modulated by the local surface characteristics of the (bio-)macromolecule. The observed cation-anion pairing preference is in excellent agreement with experimental data.

Surface Effects on Aggregation Kinetics of Amyloidogenic Peptides

The presence of surfaces influences the fibril formation kinetics of peptides and proteins. We present a systematic study of the aggregation kinetics of amyloidogenic peptides caused by different surfaces using molecular simulations of model peptides and thioflavin T fluorescence experiments. Increasing the monomer-surface attraction affects the nucleation and growth of small oligomers in a nonlinear manner: Weakly attractive surfaces lead to retardation; strongly attractive surfaces lead to acceleration. Further, the same type of surface either accelerates or retards growth, depending on the bulk propensity of the peptide to form fibrils: An attractive surface retards fibril formation of peptides with a high tendency for fibril formation, while the same surface accelerates fibril formation of peptides with a low propensity for fibril formation. The surface effect is thus determined by the relative association propensity of peptides for the surface compared to bulk and by the surface area to protein concentration ratio. This rationalization is in agreement with the measured fibrillar growth of α-synuclein from Parkinson and amyloid β peptide from Alzheimer disease in the presence of surface area introduced in a controlled way in the form of nanoparticles. These findings offer molecular insight into amyloid formation kinetics in complex environments and may be used to tune fibrillation properties in diverse systems.

A Mesoscopic Model for Protein-Protein Interactions in Solution

Protein self-association may be detrimental in biological systems, but can be utilized in a controlled fashion for protein crystallization. It is hence of considerable interest to understand how factors like solution conditions prevent or promote aggregation. Here we present a computational model describing interactions between protein molecules in solution. The calculations are based on a molecular description capturing the detailed structure of the protein molecule using x-ray or nuclear magnetic resonance structural data. Both electrostatic and van der Waals interactions are included and the salt particles are explicitly treated allowing investigations of systems containing mono-, di-, and trivalent ions. For three different proteins-lysozyme, alpha-chymotrypsinogen, and calbindin D(9k)-we have investigated under which conditions (salt concentration, ion valency, pH, and/or solvent) the proteins are expected to aggregate via evaluation of the second virial coefficient. Good agreement is found with experimental data where available. Calbindin is investigated in more detail, and it is demonstrated how changes in solvent and/or counterion valency lead to attractive ion-ion correlation effects. For high valency counterions we have found abnormal trends in the second virial coefficient. With trivalent counterions, attraction of two negatively charged protein molecules can be favored because the repulsive term is decreased for entropic reasons due to the low number of particles present.

Water-Mediated Ion Pairing : Occurrence and Relevance

We present an overview of the studies of ion pairing in aqueous media of the past decade. In these studies, interactions between ions, and between ions and water, are investigated with relatively novel approaches, including dielectric relaxation spectroscopy, far-infrared (terahertz) absorption spectroscopy, femtosecond mid-infrared spectroscopy, and X-ray spectroscopy and scattering, as well as molecular dynamics simulation methods. With these methods, it is found that ion pairing is not a rare phenomenon only occurring for very particular, strongly interacting cations and anions. Instead, for many salt solutions and their interfaces, the measured and calculated structure and dynamics reveal the presence of a distinct concentration of contact ion pairs (CIPs), solvent shared ion pairs (SIPs), and solvent-separated ion pairs (2SIPs). We discuss the importance of specific ion-pairing interactions between cations like Li(+) and Na(+) and anionic carboxylate and phosphate groups for the structure and functioning of large (bio)molecular systems.

Ion-specific thermodynamics of multicomponent electrolytes: A hybrid HNC/MD approach

Using effective infinite dilution ion-ion interaction potentials derived from explicit-water molecular dynamics (MD) computer simulations in the hypernetted-chain (HNC) integral equation theory we calculate the liquid structure and thermodynamic properties, namely, the activity and osmotic coefficients of various multicomponent aqueous electrolyte mixtures. The electrolyte structure expressed by the ion-ion radial distribution functions is for most ions in excellent agreement with MD and implicit solvent Monte Carlo (MC) simulation results. Calculated thermodynamic properties are also represented consistently among these three methods. Our versatile HNC/MD hybrid method allows for a quick prediction of the thermodynamics of multicomponent electrolyte solutions for a wide range of concentrations and an efficient assessment of the validity of the employed MD force-fields with possible implications in the development of thermodynamically consistent parameter sets.

Adsorption of Unstructured Protein beta-Casein to Hydrophobic and Charged Surfaces

In this Monte Carlo simulation study we use mesoscopic modeling to show that β-casein, an unstructured milk protein, adsorbs to surfaces not only due to direct electrostatic and hydrophobic interactions but also due to structural rearrangement and charge regulation due to proton uptake and release. β-casein acts as an amphiphilic chameleon, changing properties according to the chemical environment, and binding is observed to both positively and negatively charged surfaces. The binding mechanisms, however, are fundamentally different. A detailed, per-residue-level analysis shows that the adsorption process is controlled by a few very specific regions of the protein and that these change dramatically with pH. Caseins, being the most abundant proteins in milk, are crucial for the properties of fermented dairy products, such as nutrition, texture, and viscosity, but may also influence adhesion to packaging materials. The latter leads to product losses of about 10%, leading to economical and environmental problems.

Charge-Induced Patchy Attractions between Proteins

Static light scattering (SLS) combined with structure-based Monte Carlo (MC) simulations provide new insights into mechanisms behind anisotropic, attractive protein interactions. A nonmonotonic behavior of the osmotic second virial coefficient as a function of ionic strength is here shown to originate from a few charged amino acids forming an electrostatic attractive patch, highly directional and complementary. Together with Coulombic repulsion, this attractive patch results in two counteracting electrostatic contributions to the interaction free energy which, by operating over different length scales, is manifested in a subtle, salt-induced minimum in the second virial coefficient as observed in both experiment and simulations.

Anisotropic Interactions in Protein Mixtures: Self Assembly and Phase Behavior in Aqueous Solution

Recent experimental studies show that oppositely charged proteins can self-assemble to form seemingly stable microspheres in aqueous salt solutions. We here use parallel tempering Monte Carlo simulations to study protein phase separation of lysozyme/α-lactalbumin mixtures and show that anisotropic electrostatic interactions are important for driving protein self-assembly. In both dilute and concentrated protein phases, the proteins strongly align according to their charge distribution. While this alignment can be greatly diminished by a single point mutation, phase separation is completely suppressed when neglecting electrostatic anisotropy. The results highlight the importance of subtle electrostatic interactions even in crowded biomolecular environments where other short-ranged forces are often thought to dominate.