Computational Approaches to Explore Bacterial Toxin Entry into the Host Cell

Many bacteria secrete toxic protein complexes that modify and disrupt essential processes in the infected cell that can lead to cell death. To conduct their action, these toxins often need to cross the cell membrane and reach a specific substrate inside the cell. The investigation of these protein complexes is essential not only for understanding their biological functions but also for the rational design of targeted drug delivery vehicles that must navigate across the cell membrane to deliver their therapeutic payload. Despite the immense advances in experimental techniques, the investigations of the toxin entry mechanism have remained challenging. Computer simulations are robust complementary tools that allow for the exploration of biological processes in exceptional detail. In this review, we first highlight the strength of computational methods, with a special focus on all-atom molecular dynamics, coarse-grained, and mesoscopic models, for exploring different stages of the toxin protein entry mechanism. We then summarize recent developments that are significantly advancing our understanding, notably of the glycolipid–lectin (GL-Lect) endocytosis of bacterial Shiga and cholera toxins. The methods discussed here are also applicable to the design of membrane-penetrating nanoparticles and the study of the phenomenon of protein phase separation at the surface of the membrane. Finally, we discuss other likely routes for future development.

Inverse design of mesoscopic models for compressible flow using the Chapman-Enskog analysis

In this paper, based on simplified Boltzmann equation, we explore the inverse-design of mesoscopic models for compressible flow using the Chapman-Enskog analysis. Starting from the single-relaxation-time Boltzmann equation with an additional source term, two model Boltzmann equations for two reduced distribution functions are obtained, each then also having an additional undetermined source term. Under this general framework and using Navier-Stokes-Fourier (NSF) equations as constraints, the structures of the distribution functions are obtained by the leading-order Chapman-Enskog analysis. Next, five basic constraints for the design of the two source terms are obtained in order to recover the NSF system in the continuum limit. These constraints allow for adjustable bulk-to-shear viscosity ratio, Prandtl number as well as a thermal energy source. The specific forms of the two source terms can be determined through proper physical considerations and numerical implementation requirements. By employing the truncated Hermite expansion, one design for the two source terms is proposed. Moreover, three well-known mesoscopic models in the literature are shown to be compatible with these five constraints. In addition, the consistent implementation of boundary conditions is also explored by using the Chapman-Enskog expansion at the NSF order. Finally, based on the higher-order Chapman-Enskog expansion of the distribution functions, we derive the complete analytical expressions for the viscous stress tensor and the heat flux. Some underlying physics can be further explored using the DNS simulation data based on the proposed model.

Mesoscopic Characteristics on Cracks of Three-Point Bending RC Beam with Corroded Reinforcement

The RC beam usually works under the combined action of external loads and corrosion expansion pressures, and the RC beams without corrosion of reinforcements have good mechanical performance. In this study, the mesoscopic models of the three-point bending RC beams with different aggregates, different aggregate contents, and different corrosion expansion pressures were built. The plastic strain and the deflection are analyzed. The results show that the cracks of the RC beam with polygon aggregates are more dispersed than circle aggregates. As the aggregate content increases, the maximum plastic strain and maximum deflection of the RC beam decrease. The aggregate contents increased from 25% to 35%, the maximum plastic strain decreased from 3.4 × 10−3 to 2.1 × 10−3, and the maximum deflection of the lower boundary of the beam decreased from 0.005 m to 0.004 m. Furthermore, the corrosion expansion pressure makes the plastic strain increase in the concrete cover.

Salt Dependent Mesoscopic Model for RNA with Multiple Strand Concentrations

Mesoscopic models can be used for the description of the thermodynamic properties of RNA duplexes. With the use of experimental melting temperatures, its parametrization can provide important insights into its hydrogen bonds and stacking interactions as has been done for high sodium concentrations. However, the RNA parametrization for lower salt concentrations is still missing due to the limited amount of published melting temperature data. While the Peyrard-Bishop (PB) parametrization was found to be largely independent of strand concentrations, it requires that all temperatures are provided at the same strand concentrations. Here we adapted the PB model to handle multiple strand concentrations and in this way we were able to make use of an experimental set of temperatures to model the hydrogen bond and stacking interactions at low and intermediate sodium concentrations. For the parametrizations we make a distinction between terminal and internal base pairs, and the resulting potentials were qualitatively similar as we obtained previously for DNA. The main difference from DNA parameters, was the Morse potentials at low sodium concentrations for terminal r(AU) which is stronger than d(AT), suggesting higher hydrogen bond strength.

Salt Dependent Mesoscopic Model for RNA with Multiple Strand Concentrations

Mesoscopic models can be used for the description of the thermodynamic properties of RNA duplexes. With the use of experimental melting temperatures, its parametrization can provide important insights into its hydrogen bonds and stacking interactions as has been done for high sodium concentrations. However, the RNA parametrization for lower salt concentrations is still missing due to the limited amount of published melting temperature data. While the Peyrard-Bishop (PB) parametrization was found to be largely independent of strand concentrations, it requires that all temperatures are provided at the same strand concentrations. Here we adapted the PB model to handle multiple strand concentrations and in this way we were able to make use of an experimental set of temperatures to model the hydrogen bond and stacking interactions at low and intermediate sodium concentrations. For the parametrizations we make a distinction between terminal and internal base pairs, and the resulting potentials were qualitatively similar as we obtained previously for DNA. The main difference from DNA parameters, was the Morse potentials at low sodium concentrations for terminal r(AU) which is stronger than d(AT), suggesting higher hydrogen bond strength.

Diauxic Growth at the Mesoscopic Scale

In the present paper, we study a diauxic growth that can be generated by a class of model at the mesoscopic scale. Although the diauxic growth can be related to the macroscopic scale, similarly to the logistic scale, one may ask whether models on mesoscopic or microscopic scales may lead to such a behavior. The present paper is the first step towards the developing of the mesoscopic models that lead to a diauxic growth at the macroscopic scale. We propose various nonlinear mesoscopic models conservative or not that lead directly to some diauxic growths.

A general framework for the inverse design of mesoscopic models based on the Boltzmann equation

In this paper, we present a general framework for the inverse-design of mesoscopic models based on the Boltzmann equation. Starting from the single-relaxation-time Boltzmann equation with an additional source term, two model Boltzmann equations for two reduced distribution functions are obtained, each then also having an additional undetermined source term. Under this general framework and using Navier-Stokes-Fourier (NSF) equations as constraints, the structures of the distribution functions are obtained by the leading-order Chapman-Enskog analysis. Next, five basic constraints for the design of the two source terms are obtained in order to recover the Navier-Stokes-Fourier system in the continuum limit. These constraints allow for adjustable bulk-to-shear viscosity ratio, Prandtl number as well as a thermal energy source. The specific forms of the two source terms can be determined through proper physical considerations and numerical implementation requirements. By employing the truncated Hermite expansion, one design for the two source terms is proposed. Moreover, three well-known mesoscopic models in the literature are shown to be compatible with these five constraints. In addition, the consistent implementation of boundary conditions is also explored by using the Chapman-Enskog expansion at the NSF order. Finally, based on the higher-order Chapman-Enskog expansion of the distribution functions, we derive the complete analytical expressions for the viscous stress tensor and the heat flux. Some underlying physics can be further explored under this framework.