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In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aß amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from αhelix to ß-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, ß-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of ß-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation. [ABSTRACT FROM AUTHOR]

Expansion of polyglutamine (polyQ) beyond the pathogenic threshold (35–40 Gln) is associated with several neurodegenerative diseases including Huntington’s disease, several forms of spinocerebellar ataxias and spinobulbar muscular atrophy. To determine the structure of polyglutamine aggregates we perform replica-exchange molecular dynamics simulations coupled with the optimized potential for effective peptide forcefield. Using a range of temperatures from 250 to 700 K, we study the aggregation kinetics of the polyglutamine monomer and dimer with chain lengths from 30 to 50 residues. All monomers show a similar structural change at the same temperature from α-helical structure to random coil, without indication of any significant β-strand. For dimers, by contrast, starting from random structures, we observe spontaneous formation of antiparallel β-sheets and triangular and circular β-helical structures for polyglutamine with 40 residues in a 400 ns 50 temperature replica-exchange molecular dynamics simulation (total integrated time 20 μs). This ∼32 Å diameter structure reorganizes further into a tight antiparallel double-stranded ∼22 Å nanotube with 22 residues per turn close to Perutz’ model for amyloid fibers as water-filled nanotubes. This diversity of structures suggests the existence of polymorphism for polyglutamine with possibly different pathways leading to the formation of toxic oligomers and to fibrils. [ABSTRACT FROM AUTHOR]

A newly proposed theory [R. Laghaei et al., J. Chem. Phys. 124, 154502 (2006)] was extended to polyatomics and applied to compute the density and temperature dependence of the effective site diameters of carbon disulfide fluids. The generic van der Waals (GvdW) theory was also extended to polyatomics in order to calculate the GvdW parameters and the molecular free volume using the effective site diameters as the repulsion-attraction separation distance. A three-site Lennard-Jones potential available in the literature was slightly modified and used in Monte Carlo simulations to obtain the functions appearing in the effective site diameter and GvdW expressions. The interaction potential was examined to reproduce the fluid phase thermodynamic properties using Gibbs ensemble Monte Carlo simulations and also the equation of state in the liquid phase using NVT Monte Carlo (NVT-MC) simulations. Comparison between the simulation results and experimental data shows excellent agreement for the densities of the coexisting phases, the vapor pressure, properties of the predicted critical point, and the equation of state. NVT-MC simulations were performed over a wide range of densities and temperatures in sub- and supercritical regions to compute the effective site diameters, the GvdW parameters, and the molecular free volume. The molecular structure in terms of the site-site pair correlation functions, the density dependence of the effective site diameters, and the density and temperature dependence of the GvdW parameters and molecular free volume were studied and discussed. The GvdW parameters were fitted to empirical expressions as a function of density and temperature. The computed molecular free volume will be used in future investigations to study the transport properties of carbon disulfide. [ABSTRACT FROM AUTHOR]

A quantum mechanical derived ab initio interaction potential for the argon dimer was tested in molecular simulations to reproduce the thermophysical properties of the vapor-liquid phase equilibria using the Gibbs ensemble Monte Carlo simulations as well as the liquid and supercritical equation of state using the NVT Monte Carlo simulations. The ab initio interaction potential was taken from the literature. A recently developed theory [R. Laghaei et al., J. Chem. Phys. 124, 154502 (2006)] was used to compute the effective diameters of argon in fluid phases and the results were subsequently applied in the generic van der Waals theory to compute the free volume of argon. The calculated densities of the coexisting phases, the vapor pressure, and the equation of state show excellent agreement with experimental values. The effective diameters and free volumes of argon are given over a wide range of densities and temperatures. An empirical formula was used to fit the effective diameters as a function of density and temperature. The computed free volume will be used in future investigations to calculate the transport properties of argon. [ABSTRACT FROM AUTHOR]

In the previous papers applying the generic van der Waals equation of state the mean excluded volume was defined with the contact diameter of particles at which the potential energy is equal to zero—the size parameter in the case of the Lennard-Jones potential. This parameter appears as the upper limit of the integral for the generic van der Waals parameter B (mean excluded volume divided by the density) in the generic van der Waals equation of state. Since the choice is not unique, in this paper we reexamine the manner of defining the upper limit and propose another choice for the upper limit. We also propose an interpretation of the free volume overlap factor α appearing in the free volume theory of diffusion and a method of estimating it in terms of the intermolecular potential energy only. It is shown that with the so-estimated free volume overlap factor and the new choice of the upper limit of the integral for B the self-diffusion coefficient in the modified free volume theory of diffusion not only acquires a better accuracy than before, but also becomes calculable in terms of only the intermolecular interaction potential without an adjustable parameter. We also assess some of effective diameters of molecules proposed in the literature for their ability to predict the self-diffusion coefficient within the framework of the modified free volume theory of diffusion. [ABSTRACT FROM AUTHOR]

In this paper the thermal conductivity of the Lennard-Jones fluid is calculated by applying the combination of the density-fluctuation theory, the modified free volume theory of diffusion, and the generic van der Waals equation of state. A Monte Carlo simulation method is used to compute the equilibrium pair-correlation function necessary for computing the mean free volume and the coefficient in the potential-energy and virial contributions to the thermal conductivity. The theoretical results are compared with our own molecular dynamics simulation results and with those reported in the literature. They agree in good accuracy over wide ranges of density and temperature examined in molecular dynamics simulations. Thus the combined theory represents a molecular theory of thermal conductivity of the Lennard-Jones fluid and by extension simple fluids, which enables us to compute the nonequilibrium quantity by means of the Monte Carlo simulations for the equilibrium pair-correlation function. [ABSTRACT FROM AUTHOR]

The generalized Boltzmann equation for simple dense fluids gives rise to the stress tensor evolution equation as a constitutive equation of generalized hydrodynamics for fluids far removed from equilibrium. It is possible to derive a formula for the non-Newtonian shear viscosity of the simple fluid from the stress tensor evolution equation in a suitable flow configuration. The non-Newtonian viscosity formula derived is applied to calculate the non-Newtonian viscosity as a function of the shear rate by means of statistical mechanics in the case of the Lennard-Jones fluid. For that purpose we have used the density-fluctuation theory for the Newtonian viscosity, the modified free volume theory for the self-diffusion coefficient, and the generic van der Waals equation of state to compute the mean free volume appearing in the modified free volume theory. Monte Carlo simulations are used to calculate the pair-correlation function appearing in the generic van der Waals equation of state and shear viscosity formula. To validate the Newtonian viscosity formula obtained we first have examined the density and temperature dependences of the shear viscosity in both subcritical and supercritical regions and compared them with molecular-dynamic simulation results. With the Newtonian shear viscosity and thermodynamic quantities so computed we then have calculated the shear rate dependence of the non-Newtonian shear viscosity and compared it with molecular-dynamics simulation results. The non-Newtonian viscosity formula is a universal function of the product of reduced shear rate (γ*) times reduced relaxation time (γ*) that is independent of the material parameters, suggesting a possibility of the existence of rheological corresponding states of reduced density, temperature, and shear rate. When the simulation data are reduced appropriately and plotted against &#03C4;*e&#x03B3* they are found clustered around the reduced (universal) non-Newtonian viscosity formula. Thus we now have a molecular theory of non-Newtonian shear viscosity for the Lennard-Jones fluid, which can be implemented with a Monte Carlo simulation method for the pair-correlation function. [ABSTRACT FROM AUTHOR]

The Matteoli-Mansoori empirical formula is applied for the pair correlation function of simple fluids obeying the Lennard-Jones potential to calculate reduced self-diffusion coefficients on the basis of the modified free volume theory. It is shown that Matteoli-Mansoori empirical formula yields sufficiently accurate self-diffusion coefficients in the supercritical regime, provided that the minimum free volume activating diffusion is estimated with the classical turning point of binary collision at the mean relative kinetic energy.

The density functional theory of transport coefficients are applied to carbon dioxide and the shear viscosity of carbon dioxide s computed without using the empirical approach. The self-diffusion coefficients thus computed are used to compute the density and temperature dependence of the shear viscosity of liquid carbon dioxide by employing the density fluctuation theory formula for shear viscosity.

The shear viscosity formula derived by the density functional theory is computed for argon, krypton, and methane by using the self-diffusion coefficients derived in the modified free volume theory with the help of the generic van der Waals equation. The theory is successfully tested in comparison with experimental data for self-diffusion coefficients and shear viscosity for argon, krypton, and methane.

We carry out extensive computer simulations to study the phase equilibrium, thermodynamics, and diffusion coefficient of three-center Lennard-Jones (3CLJ) fluids with an emphasis on the effects of bond angle on these properties. We take into account several bond angles ranging from θ0 = 60 to 180 degrees and two equilibrium bond elongations le = 1.0 and 0.5 (in Lennard-Jones length unit). Moreover, we study the fully flexible (FF) 3CLJ fluids for molecules with bond length 1.0. Gibbs ensemble Monte Carlo (MC) simulations are performed to compute the densities of the vapor-liquid coexisting phases and the vapor pressure, and direct three-phase (vapor-liquid-vapor) molecular dynamics (MD) simulations are carried out to calculate the surface tension. We then apply constant NVT MC simulations to obtain the internal energy, the pressure, and the pair correlation function, and utilize equilibrium MD simulations to compute the diffusion coefficient of systems with le = 1.0. In addition to MD simulations, the modified Cohen-Turnbull (mCT) theory is used to to compute the diffusion coefficient and the mean free volume appearing in the mCT relation is provided by the results of the Generic van der Waals (GvdW) theory. We show that the mCT theory is capable of reproducing the MD simulation values quite well over a wide range of density with slight overestimations at medium range. The angle dependence of different thermophysical properties are analyzed and discussed in details. [ABSTRACT FROM AUTHOR]

Influx of ferrous ions from the cytoplasmthrough 3-fold poresin the shell of ferritin protein is computed using a 3-dimensionalPoisson–Nernst–Planck electrodiffusion model, with inputssuch as the pore structure and the diffusivity profile of permeantFe2+ions extracted from all-atom molecular dynamics (MD)simulations. These calculations successfully reproduce experimentalestimates of the transit time of Fe2+through the ferritincoat, which is on the millisecond time scale and hence much too longto be directly simulated via all-atom MD. This is also much longerthan the typical time scale for ion transit in standard membrane spanningion channels whose pores bear structural similarity to that of the3-fold ferritin pore. The slow time scale for Fe2+transportthrough ferritin pores is traced to two features that distinguishthe ferritin pore system from standard ion channels, namely, (i) verylow concentration of cytoplasmic Fe2+under physiologicalconditions and (ii) very small internal diffusion coefficients forions inside the ferritin pore resulting from factors that includethe divalent nature of Fe2+and two rings of negativelycharged amino acids surrounding a narrow geometric obstruction withinthe ferritin pore interior. [ABSTRACT FROM AUTHOR]

The Amyloid-beta protein is related to Alzheimer’sdisease, and various experiments have shown that oligomers as smallas the dimer are cytotoxic. Two alloforms are mainly produced: Aβ1–40and Aβ1–42. They have verydifferent oligomer distributions, and it was recently suggested, fromexperimental studies, that this variation may originate from structuraldifferences in their dimer structures. Little structural informationis available on the Aβ dimer, however, and to complement experimentalobservations, we simulated the folding of the wild-type Aβ1–40and Aβ1–42dimers as wellas the mutated Aβ1–40(D23N) dimer using anaccurate coarse-grained force field coupled to Hamiltonian-temperaturereplica exchange molecular dynamics. The D23N variant impedes thesalt-bridge formation between D23 and K28 seen in the wild-type Aβ,leading to very different fibrillation properties and final amyloidfibrils. Our results show that the Aβ1–42dimerhas a higher propensity than the Aβ1–40dimerto form β-strands at the central hydrophobic core (residues17–21) and at the C-terminal (residues 30–42), whichare two segments crucial to the oligomerization of Aβ. The freeenergy landscape of the Aβ1–42dimer is alsobroader and more complex than that of the Aβ1–40dimer. Interestingly, D23N also impacts the free energy landscapeby increasing the population of configurations with higher β-strandpropensities when compared against Aβ40. In addition,while Aβ1–40(D23N) displays a higher β-strandpropensity at the C-terminal, its solvent accessibility does not changewith respect to the wild-type sequence. Overall, our results showthe strong impact of the two amino acids Ile41-Ala42 and the salt-bridgeD23–K28 on the folding of the Aβ dimer. [ABSTRACT FROM AUTHOR]

Current approaches aimed at determining the free energy surface of all-atom medium-size proteins in explicit solvent are slow and are not sufficient to converge to equilibrium properties. To ensure a proper sampling of the configurational space, it is preferable to use reduced representations such as implicit solvent and/or coarse-grained protein models, which are much lighter computationally. Each model must be verified, however, to ensure that it can recover experimental structures and thermodynamics. Here we test the coarse-grained implicit solvent OPEP model with replica exchange molecular dynamics (REMD) on six peptides ranging in length from 10 to 28 residues: two alanine-based peptides, the second beta-hairpin from protein G, the Trp-cage and zinc-finger motif, and a dimer of a coiled coil peptide. We show that REMD-OPEP recovers the proper thermodynamics of the systems studied, with accurate structural description of the beta-hairpin and Trp-cage peptides (within 1-2 A from experiments). The light computational burden of REMD-OPEP, which enables us to generate many hundred nanoseconds at each temperature and fully assess convergence to equilibrium ensemble, opens the door to the determination of the free energy surface of larger proteins and assemblies.

A quantum mechanical derived ab initio interaction potential for the argon dimer was tested in molecular simulations to reproduce the thermophysical properties of the vapor-liquid phase equilibria using the Gibbs ensemble Monte Carlo simulations as well as the liquid and supercritical equation of state using the NVT Monte Carlo simulations. The ab initio interaction potential was taken from the literature. A recently developed theory [R. Laghaei et al., J. Chem. Phys. 124, 154502 (2006)] was used to compute the effective diameters of argon in fluid phases and the results were subsequently applied in the generic van der Waals theory to compute the free volume of argon. The calculated densities of the coexisting phases, the vapor pressure, and the equation of state show excellent agreement with experimental values. The effective diameters and free volumes of argon are given over a wide range of densities and temperatures. An empirical formula was used to fit the effective diameters as a function of density and temperature. The computed free volume will be used in future investigations to calculate the transport properties of argon.