Gergely Tóth

On the Mechanism of Nonspecific Inhibitors of Protein Aggregation: Dissecting the Interactions of α-Synuclein with Congo Red and Lacmoid

Increasing evidence links the misfolding and aberrant self-assembly of proteins with the molecular events that underlie a range of neurodegenerative diseases, yet the mechanistical details of these processes are still poorly understood. The fact that many of these proteins are intrinsically unstructured makes it particularly challenging to develop strategies for discovering small molecule inhibitors of their aggregation. We present here a broad biophysical approach that enables us to characterize the mechanisms of interaction between alpha-synuclein, a protein whose aggregation is closely connected with Parkinsons disease, and two small molecules, Congo red and Lacmoid, which inhibit its fibrillization. Both compounds are found to interact with the N-terminal and central regions of the monomeric protein although with different binding mechanisms and affinities. The differences can be attributed to the chemical nature of the compounds as well as their abilities to self-associate. We further show that alpha-synuclein binding and aggregation inhibition are mediated by small oligomeric species of the compounds that interact with distinct regions of the monomeric protein. These findings provide potential explanations of the nonspecific antiamyloid effect observed for these compounds as well as important mechanistical information for future drug discovery efforts targeting the misfolding and aggregation of intrinsically unstructured proteins.

Structure and dynamics of water and hydrated ions near platinum and mercury surfaces as studied by MD simulations

Results of various MD simulations of pure water and those with either an additional lithium or iodide ion near a Pt(100), a rigid and a liquid mercury surface are reported. The potentials describing the interactions with the metal surfaces are based on ab initio calculations of a water molecule or an ion and metal clusters of different sizes. The flexible BJH and the rigid TIP4P models for water are employed and the ion-water interactions are also derived from ab initio calculations. The structure at the interfaces for pure water at the three different surfaces is described by oxygen, hydrogen and mercury atom density profiles. The effect of all three metal surfaces on the structure of the hydration shells of the lithium and the iodide ion are discussed in detail and the free energies are reported as a function of distance from the rigid mercury surface. The spectral densities of the hindered translational motions of both ions parallel and perpendicular to the Pt(100) and the liquid mercury surface are presented.

Polymorphism, crystal nucleation and growth in the phase-field crystal model in 2D and 3D

We apply a simple dynamical density functional theory, the phase-field crystal (PFC) model of overdamped conservative dynamics, to address polymorphism, crystal nucleation, and crystal growth in the diffusion-controlled limit. We refine the phase diagram for 3D, and determine the line free energy in 2D and the height of the nucleation barrier in 2D and 3D for homogeneous and heterogeneous nucleation by solving the respective Euler-Lagrange (EL) equations. We demonstrate that, in the PFC model, the body-centered cubic (bcc), the face-centered cubic (fcc), and the hexagonal close-packed structures (hcp) compete, while the simple cubic structure is unstable, and that phase preference can be tuned by changing the model parameters: close to the critical point the bcc structure is stable, while far from the critical point the fcc prevails, with an hcp stability domain in between. We note that with increasing distance from the critical point the equilibrium shapes vary from the sphere to specific faceted shapes: rhombic dodecahedron (bcc), truncated octahedron (fcc), and hexagonal prism (hcp). Solving the equation of motion of the PFC model supplied with conserved noise, solidification starts with the nucleation of an amorphous precursor phase, into which the stable crystalline phase nucleates. The growth rate is found to be time dependent and anisotropic; this anisotropy depends on the driving force. We show that due to the diffusion-controlled growth mechanism, which is especially relevant for crystal aggregation in colloidal systems, dendritic growth structures evolve in large-scale isothermal single-component PFC simulations. An oscillatory effective pair potential resembling those for model glass formers has been evaluated from structural data of the amorphous phase obtained by instantaneous quenching. Finally, we present results for eutectic solidification in a binary PFC model.

On the uniqueness of the Reverse Monte Carlo simulation. I. Simple liquids, partial radial distribution functions

Partial radial distribution functions of standard Monte Carlo simulations were used as input for Reverse Monte Carlo simulation, a novel method for structural modeling. From detailed comparison of the two independent (MC and RMC) particle configurations it has turned out that sufficiently close agreement in radial distribution functions involves deeper structural similarities. RMC results, i.e., particle configurations produced by RMC upon the basis of partial radial distribution functions, are therefore applicable for detailed analysis of the structure, giving new prospects for data evaluation in neutron diffraction method. As a result of extensive Reverse Monte Carlo simulations of this work some new aspects of the technique itself could be revealed.

Abinitio pair potential parameter set for the interaction of a rigid and a flexible water model and the complete series of the halides and alkali cations

The ab initio calculations were performed at the quantum chemical levels of the second and fourth order Moller–Plesset perturbation theory. The binding energies were corrected for the basis set superposition error. Exactly 420 different ion–water configurations were chosen for each ion to scan the potential surface entirely. The parametrized analytical potential functions, the radial distribution functions, and the solvation internal energies obtained by molecular dynamics simulations were compared to previous simulations and experimental results.

Amorphous Nucleation Precursor in Highly Nonequilibrium Fluids

Dynamical density-functional simulations reveal structural aspects of crystal nucleation in undercooled liquids: The first appearing solid is amorphous, which promotes the nucleation of bcc crystals but suppresses the appearance of the fcc and hcp phases. These findings are associated with features of the effective interaction potential deduced from the amorphous structure.

SCF calculations of the interactions of alkali and halide ions with the mercury surface

From extensive ab initio calculations on the interactions between mercury clusters and alkali and halide ions we have derived analytical pair-potential functions for the interaction between the ion and an extended mercury (111) surface. A novel correction scheme is proposed in order to reduce the shortcomings of cluster model. A preferred adsorption above the twofold bridge site was found for Li+ and Na+ and above the threefold hollow site for all other ions. The ab initio results have been fitted to analytical functions that can be used in computer simulations.

Molecular dynamics study of an iodide and a lithium ion at the water-liquid mercury interface

Abstract The ion-mercury potentials derived from ab initio calculations of an ion and a mercury cluster consisting of nine or ten atoms are applied in molecular dynamics simulations. The flexible BJH water model and a mercury-mercury potential derived from pseudopotential theory are employed. The other potentials are based on ab initio calculations. The structural properties at the interface are described by the ion, oxygen, hydrogen and mercury density profiles and the ion-oxygen, ion-hydrogen and ion-mercury radial distribution functions. The mercury-mercury potential allows analysis of the ion-induced rearrangements of the mercury atoms at the surface. The spectral densities of the hindered translational motions of the ions parallel and perpendicular to the surface are reported. The results are compared with those at a Pt(100) surface.

Conceptual and technical improvement of the reverse Monte Carlo algorithm

We performed Metropolis Monte Carlo and a comprehensive set of reverse Monte Carlo simulations using the same Lennard-Jones liquid to analyze the algorithmic correctness of the latter method. We found that the present reverse Monte Carlo technique is biased because it samples relatively disordered arrangements more often than ordered ones, which leads to a poor acceptance ratio and questionable relevance to the structure of the real system. On the basis of our results, we propose changes in the algorithm. To remove the deficiency we applied a combined acceptance criterion, which in addition to the very restrictive difference minimization procedure, uses an entropy related factor to select from the possible configurations. Further improvement can be achieved if the simulations are performed on the structure factor and the radial distribution function simultaneously. If the radial distribution function is the target function, incorporation of the r-dependent measurement error in the acceptance criterion is ...

An iterative scheme to derive pair potentials from structure factors and its application to liquid mercury

We developed an iterative scheme to optimize classical mechanical pair-potential parameters of liquids on the basis of diffraction data. An iterative step, similarly as in our previous method, consists of two parts: A classical mechanical simulation with an assumed pair potential and the modification of the potential using the experimental data and quantities calculated in the simulation. The modification part is formulated according to the Gauss–Newton–Marquardt nonlinear parameter fit. The method is used to get tabulated potentials, and seems to be robust also in the case of a fit of few hundred parameters simultaneously. The method keeps the advantages of our previous procedure: The fitted function is the measured structure factor, the Fourier transformation is applied with controllable error, the total functions are determined from the partial ones to avoid the solution of linear equations, and the error of the experiments can be taken into account explicitly. The theoretical justification of the meth...