Prediction of self-diffusion coefficients of chemically diverse pure liquids by all-atom molecular dynamics simulations.

Molecular self-diffusion coefficients underlie various kinetic properties of the liquids involved in chemistry, physics, and pharmaceutics. In this study, 547 self-diffusion coefficients are calculated based on all-atom molecular dynamics (MD) simulations of 152 diverse pure liquids at various temperatures employing the OPLS4 force field. The calculated coefficients are compared with experimental data (424 extracted from the literature and 123 newly measured by pulsed-field gradient nuclear magnetic resonance). The calculations well agree with the experimental values. The determination coefficient and root mean square error between the observed and calculated logarithmic self-diffusion coefficients of the 547 entries are 0.931 and 0.213, respectively, demonstrating that the MD calculation can be an excellent industrial tool for predicting, for example, molecular transportation in liquids such as the diffusion of active ingredients in biological and pharmaceutical liquids. The self-diffusion coefficients collected in this study are compiled into a database for broad researches including artificial intelligence calculations.

All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution.

Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog drugs, which are triphosphorylated and negatively charged in the cell, approach the capsid via diffusion and are absorbed into it. In this study, we performed a long-time molecular dynamics calculation of the entire HBV capsid containing pregenome RNA to investigate the interactions between the capsid and negatively charged substances. Electric field analysis demonstrated that negatively charged substances can approach the HBV capsid by thermal motion, avoiding spikes. The substances then migrate all over the floor of the HBV capsid. Finally, they find pores through which they can pass through the HBV capsid shell. Free energy profiles were calculated along these pores for small ions to understand their permeability through the pores. Anions (Cl-) showed higher free energy barriers than cations (Na+ and K+) through all pores, and the permeation rate of Cl- was eight times slower than that of K+ or Na+. Furthermore, the ions were more stable in the capsid than in the bulk water. Thus, the HBV capsid exerts ion selectivity for uptake and provides an environment for ions, such as nucleotides and nucleotide analog drugs, to be stabilized within the capsid.

Exact long-range Coulombic energy calculation for net charged systems neutralized by uniformly distributed background charge using fast multipole method and its application to efficient free energy calculation.

In molecular dynamics (MD) calculations of the free energies of ions and ionic molecules, we often encounter net charged molecular systems where the electrical neutrality condition is broken. This charge causes a problem in the evaluation of long-range Coulombic interactions under periodic boundary conditions. A standard remedy for this problem is to consider a hypothetical homogeneous background charge density to neutralize the total system. Here, we present a new expression for the evaluation of Coulombic interactions for such systems including background charge using the fast multipole method (FMM). Furthermore, an efficient scheme is developed to evaluate solute-solvent interaction energies using the FMM, reducing the computational burden for the far-field part. We calculate the hydration free energies of Mg2+, Na+, and Cl- ions dissolved in a neutral solvent using the new expression. The calculated free energies show good agreement with the results obtained using the well-established particle mesh Ewald method. This demonstrates the validity of the proposed expression. This work should make a contribution to highly parallelized MD calculations for large-scale charged systems (particularly, those with over million particles).

Characteristics of azole-resistant Aspergillus fumigatus attached to agricultural products imported to Japan.

Due to the increase in the number of azole-resistant Aspergillus fumigatus, there is an urgent need of data to predict future trends and prevent further spreading. The intercountry transfer of resistant A. fumigatus on plant bulbs have been reported. We investigated existence and characteristics of resistant isolates attached to agricultural products imported to Japan. We purchased 292 samples in Japan. All samples were screened for the existence of azole-resistant A. fumigatus. For positive isolates, minimum inhibitory concentrations of the drugs were determined. We also analyzed Cyp51A, Hmg1, and Erg6 mutations of these isolates and conducted microsatellite genotyping. Fourteen azole-resistant isolates were detected, of which 13 were cultured from flower bulbs imported from the Netherlands. Among them 5 were from 11 bulbs of Hippeastrum (45.5%), 5 were from 24 bulbs of Gladiolus (20.8%), 2 were from 4 bulbs of Ixia (50.0%), and 1 was from 22 bulbs of Tulipa (4.5%). Only 1 resistant isolate was cultured from the 10 bulbs of Narcissus (10.0%) originating in Japan. Various novel mutations including Y121F/T289A in Cyp51A with no tandem repeat in promoter region were discovered from imported strains. Our study provides important data showing that agricultural imports provide a possible route for their intercontinental spread and raises the concern that strains harboring highly diverse Cyp51A mutations might increase in clinical settings in the future.

Cellular prion protein targets amyloid-ß fibril ends via its C-terminal domain to prevent elongation.

Oligomeric forms of the amyloid-ß (Aß) peptide are thought to represent the primary synaptotoxic species underlying the neurodegenerative changes seen in Alzheimer's disease. It has been proposed that the cellular prion protein (PrPC) functions as a cell-surface receptor, which binds to Aß oligomers and transduces their toxic effects. However, the molecular details of the PrPC-Aß interaction remain uncertain. Here, we investigated the effect of PrPC on polymerization of Aß under rigorously controlled conditions in which Aß converts from a monomeric to a fibrillar state via a series of kinetically defined steps. We demonstrated that PrPC specifically inhibited elongation of Aß fibrils, most likely by binding to the ends of growing fibrils. Surprisingly, this inhibitory effect required the globular C-terminal domain of PrPC, which has not been previously implicated in interactions with Aß. Our results suggest that PrPC recognizes structural features common to both Aß oligomers and fibril ends and that this interaction could contribute to the neurotoxic effect of Aß aggregates. Additionally, our results identify the C terminus of PrPC as a new and potentially more druggable molecular target for treating Alzheimer's disease.

Characterization of dynamics and mechanism in the self-assembly of AOT reverse micelles.

Reverse micelles (RMs) are recognized as a paradigm of molecular self-assembly and used in a variety of applications, such as chemical synthesis and molecular structure refinement. Nevertheless, many fundamental properties including their equilibrium size distribution, internal structure, and mechanism of self-assembly remain poorly understood. To provide an enhanced microscopic understanding of the assembly process and resulting structural distribution, we perform multiple nonequilibrium molecular dynamics simulations of dioctyl sulfosuccinate sodium salt (AOT) RM assembly, quantifying RM size, water core structure, and dynamics. Rapid assembly of smaller RM from a random mixture is observed to establish a constant AOT water loading within a nanosecond consistent with a diffusion-adsorption mechanism validated through the Monte-Carlo simulation of a model system. The structure of RM water cores and RM molecular volume during RM assembly is characterized during the AOT assembly process. A moment-closure equation is developed from a novel master equation model to elucidate the elementary events underlying the AOT self-assembly process. The resulting kinetic model is used to explore the role of monomer addition and dissociation, RM association and dissociation, and RM collision-induced exchange, all dependent on average RM size, which provides fundamental insight regarding the mechanisms and time scales for AOT RM self-assembly. The nascent dynamics that rapidly establish water loading, intermediate time scales of RM fusion, and longer time scale dynamics of inter-RM exchange essential in establishing the equilibrium condition are quantified through these kinetic models. Overall, this work provides insight into AOT RM self-assembly and provides a general theoretical framework for the analysis of the molecular self-assembly dynamics and mechanism.

Observation of helix associations for insertion of a retinal molecule and distortions of helix structures in bacteriorhodopsin.

We applied a newly proposed prediction method for membrane protein structures to bacteriorhodopsin that has distorted transmembrane helices in the native structure. This method uses an implicit membrane model, which restricts sampling space during folding in a membrane region, and includes helix bending. Replica-exchange simulations were performed with seven transmembrane helices only without a retinal molecule. Obtained structures were classified into clusters of similar structures, which correspond to local-minimum free energy states. The two lowest free energy states corresponded to a native-like structure with the correct empty space for retinal and a structure with this empty space filled with a helix. Previous experiments of bacteriorhodopsin suggested that association of transmembrane helices enables them to make a room for insertion of a retinal. Our results are consistent with these results. Moreover, distortions of helices in the native-like structures were successfully reproduced. In the distortions, whereas the locations of kinks for all helices were similar to those of Protein Data Bank's data, the amount of bends was more similar for helices away from the retinal than for those close to the retinal in the native structure. This suggests a hypothesis that the amino-acid sequence specifies the location of kinks in transmembrane helices and that the amount of distortions depends on the interactions with the surrounding molecules such as neighboring helices, lipids, and retinal.

Position-Dependent Diffusion Constant of Molecules in Heterogeneous Systems as Evaluated by the Local Mean Squared Displacement.

The authors propose a novel method to evaluate the position-dependent diffusion constant by analyzing unperturbed segments of a trajectory determined by the additional flat-bottom potential. The accuracy of this novel method is first established by studying homogeneous systems, where the reference value can be obtained by the Einstein relation. The applicability of this new method to heterogeneous systems is then demonstrated by studying a hydrophobic solute near a hydrophobic wall. The proposed method is also comprehensively compared with popular conventional methods, whereby the significance of the present method is illustrated. The novel method is powerful and useful for studying kinetics in heterogeneous systems based on molecular dynamics calculations.

Aerosol-OT Surfactant Forms Stable Reverse Micelles in Apolar Solvent in the Absence of Water.

Normal micelle aggregates of amphiphilic surfactant in aqueous solvents are formed by a process of entropically driven self-assembly. The self-assembly of reverse micelles from amphiphilic surfactant in a nonpolar solvent in the presence of water is considered to be an enthalpically driven process. Although the formation of normal and reverse surfactant micelles has been well characterized in theory and experiment, the nature of dry micelle formation, from amphiphilic surfactant in a nonpolar solvent in the absence of water, is poorly understood. In this study, a theory of dry reverse micelle formation is developed. Variation in free energy during micelle assembly is derived for the specific case of aerosol-OT surfactant in isooctane solvent using atomistic molecular dynamics simulation analyzed using the energy representation method. The existence and thermodynamic stability of dry reverse micelles of limited size are confirmed. The abrupt occurrence of monodisperse aggregates is a clear signature of a critical micelle concentration, commonly observed in the formation of normal surfactant micelles. The morphology of large dry micelles provides insight into the nature of the thermodynamic driving forces stabilizing the formation of the surfactant aggregates. Overall, this study provides detailed insight into the structure and stability of dry reverse micelles assembly in a nonpolar solvent.