Bo Svensson

Widom's method for uniform and non-uniform electrolyte solutions

We develop and apply test particle methods to calculate chemical potentials in uniform and non-uniform electrolytes using computer simulations. Our techniques are based on the well-known Widom method, but account for non-electroneutral particle fluctuations, implicitly suppressed in a usual Canonical Ensemble Monte Carlo simulation. These fluctuations are shown to contribute greatly to the Widom average for a single ionic species. We compare our results with similar Grand Canonical Monte Carlo simulations for 1:1, 2:1 and 2:2 uniform electrolytes, and 1:1 electrolytes at a charged planar interface. In general, we find good agreement between the methods, all within the statistical fluctuations. The advantages of using the test particle approaches are discussed.

Rational design of antimicrobial C3a analogues with enhanced effects against Staphylococci using an integrated structure and function-based approach.

The anaphylatoxin C3a and its inactivated derivative C3adesArg, generated during complement activation, exert direct antimicrobial effects, mediated via its C-terminal region [Nordahl et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 16879-16884]. During evolution, this region of C3a displays subtle changes in net charge, while preserving a moderate but variable amphipathicity [Pasupuleti et al. (2007) J. Biol. Chem. 282, 2520-2528]. In this study, we mimic these evolutionary changes, employing a design approach utilizing selected amino acid substitutions at strategic and structurally relevant positions in the original human C3a peptide CNYITELRRQHARASHLGLA, followed by structure-activity studies incorporating sequence-dependent QSAR models as tools for generation of C3a peptide variants with enhanced effects. While the native peptide and related amphipathic analogues of moderate positive net charge were active against the Gram-negative Escherichia coli, activity against the Gram-positive Staphylococcus aureus was primarily observed for peptides characterized by a combination of a relatively high net charge (+6-7) and a propensity to adopt an alpha-helical conformation with amphipathic character. Such increased helicity and charge also conferred activity against the fungus Candida albicans. A central histidine residue (H11), evolutionarily conserved among vertebrates, conferred high selectivity toward microbes, while substitutions with leucine rendered the peptides hemolytic. Selected C3a analogues retained their specificity against staphylococci in the presence of human plasma, while showing low cytotoxicity. The work illustrates structure-activity relationships underlying the function and specificity of antimicrobial C3a and related analogues and provides insights into the forces that drive evolution of antimicrobial peptides.

The interaction between charged aggregates in electrolyte solution. A Monte Carlo simulation study

Abstract The Monte Carlo simulation technique has been used to calculate the electrostatic force acting upon a charged aggregate outside a similarly charged wall. Contrary to intuition and existing electrostatic theories, the force is found to be attractive for some realistic values of the parameters determining the system. High surface charge density, low temperature, low relative permitivity and polyvalent neutralizing counterions are all factors that favour a net attraction between the wall and the aggregate. In some cases the resulting electrostatic attractive force is found to be an order of magnitude larger than the ordinary van der Waals attraction applied in the DLVO theory of colloidal stability. The attractive interaction is interpreted as being due to currelations between the counterions in the electric double layers.

The C-Terminal Sequence of Several Human Serine Proteases Encodes Host Defense Functions.

Serine proteases of the S1 family have maintained a common structure over an evolutionary span of more than one billion years, and evolved a variety of substrate specificities and diverse biological roles, involving digestion and degradation, blood clotting, fibrinolysis and epithelial homeostasis. We here show that a wide range of C-terminal peptide sequences of serine proteases, particularly from the coagulation and kallikrein systems, share characteristics common with classical antimicrobial peptides of innate immunity. Under physiological conditions, these peptides exert antimicrobial effects as well as immunomodulatory functions by inhibiting macrophage responses to bacterial lipopolysaccharide. In mice, selected peptides are protective against lipopolysaccharide-induced shock. Moreover, these S1-derived host defense peptides exhibit helical structures upon binding to lipopolysaccharide and also permeabilize liposomes. The results uncover new and fundamental aspects on host defense functions of serine proteases present particularly in blood and epithelia, and provide tools for the identification of host defense molecules of therapeutic interest.

On the mean spherical approximation (MSA) for colloidal systems: A comparison with results from Monte Carlo simulations

The Monte Carlo simulation technique has been used to assess the accuracy of two analytical theories, the mean spherical approximation (MSA) and the rescaled MSA (RMSA), used in colloid chemistry. The results seem to indicate that the MSA method is valid for concentrated colloids with low surface charge density. The RMSA extends the validity to dilute systems but still only for weakly charged colloids. The screened coulombic potential, originating from the DLVO-theory, used in these calculations seems to be a reasonable approximation for a monovalent supporting electrolyte but less accurate for multivalent electrolytes.

On the simulation of thermodynamic and structural properties of simple liquids

This work, which is purely methodological, demonstrates new applications of perturbation methods in computer simulations of simple liquids. Most applications are based on the calculation of bulk and local excess chemical potentials of one or several inserted test particles, using a Widom technique in the canonical ensemble. This gives a powerful tool for obtaining distribution functions, some of which are virtually impossible to determine with other techniques. Results are also presented for single‐ion activity coefficients and Donnan potentials. A perturbation approach is used to calculate thermodynamic response functions with respect to particle number, temperature, and volume changes. The applicability is exemplified by studies of hard‐sphere fluids, uniform and nonuniform electrolyte solutions within the primitive model, and screened Coulomb systems.

Simulations in planar slits at constant chemical potential

In this work we describe Monte Carlo simulations of a fluid confined between planar walls. We derive a free energy difference method (FEDM) in the isotension ensemble. We illustrate the method by varying the separation between the walls at constant chemical potential. It is shown that the FEDM is a viable alternative to grand canonical ensemble (GCE) simulations. Our method appears to be less susceptible to the difficulties that confront the simulation of confined fluids at high density in the GCE.

Inhibition of Human DHODH by 4‐Hydroxycoumarins, Fenamic Acids, and N‐(Alkylcarbonyl)anthranilic Acids Identified by Structure‐Guided Fragment Selection

A strategy that combines virtual screening and structure‐guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4‐hydroxycoumarins, fenamic acids, and N‐(alkylcarbonyl)anthranilic acids. Structure‐guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N‐(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.

Electrostatic contributions to the binding of Ca2+ in calbindin mutants: A Monte Carlo study

Monte Carlo simulation is used to calculate the free energy of binding of calcium ions to the native and several mutant forms of bovine calbindin D(9K) in salt solution. The simulations are performed in the canonical ensemble wherein free energies are calculated with a modified Widom method. The protein is modelled as a set of fixed hard spheres of fractional or unit charge with the surrounding solution as a dielectric continuum containing counterions and added salt particles. The interior of the protein is assumed to have the same dielectric permittivity as the solvent, which turns out to be an excellent approximation. Indeed, this simple model is able to predict accurately experimentally measured shifts in the calcium binding constants of up to five orders of magnitude, due to mutations and added salt.

A new algorithm for Reverse Monte Carlo simulations

We present a new algorithm for Reverse Monte Carlo (RMC) simulations of liquids. During the simulations, we calculate energy, excess chemical potentials, bond-angle distributions and three-body correlations. This allows us to test the quality and physical meaning of RMC-generated results and its limitations. It also indicates the possibility to explore orientational correlations from simple scattering experiments. The new technique has been applied to bulk hard-sphere and Lennard-Jones systems and compared to standard Metropolis Monte Carlo results.