The nature of the hydrophobic interaction varies as the solute size increases from methane's to C60's.

The hydrophobic interaction, often combined with the hydrophilic or ionic interactions, makes the behavior of aqueous solutions very rich and plays an important role in biological systems. Theoretical and computer simulation studies have shown that the water-mediated force depends strongly on the size and other chemical properties of the solute, but how it changes with these factors remains unclear. We report here a computer simulation study that illustrates how the hydrophobic pair interaction and the entropic and enthalpic terms change with the solute size when the solute-solvent weak attractive interaction is unchanged with the solute size.

Vaccine and antiviral drug promise for preventing post-acute sequelae of COVID-19, and their combination for its treatment.

Introduction: Most healthy individuals recover from acute SARS-CoV-2 infection, whereas a remarkable number continues to suffer from unexplained symptoms, known as Long COVID or post-acute COVID-19 syndrome (PACS). It is therefore imperative that methods for preventing and treating the onset of PASC be investigated with the utmost urgency.

Methods: A mathematical model of the immune response to vaccination and viral infection with SARS-CoV-2, incorporating immune memory cells, was developed.

Pair Potential between Poloxamer 407 Micelles in 14 wt % Aqueous Solution Clarifying the Sol-Gel-Sol Transition by Temperature Rise.

Poloxamer 407 (P407) is used as a safety-guaranteed, invaluable pharmaceutical nanocarrier. The aqueous solution of P407 exhibits sol-to-gel and gel-to-sol transitions, specifically during a temperature rise. Here, we develop a method to determine the pair potential between colloidal particles based primarily on experimental small-angle scattering data.

Solvation free energies of alcohols in water: temperature and pressure dependences.

Solvation free energies * of amphiphilic species, methanol and 1,2-hexanediol, are obtained as a function of temperature or pressure based on molecular dynamics simulations combined with efficient free-energy calculation methods. In general, * of an amphiphile can be divided into and , the nonpolar and electrostatic contributions, and the former is further divided into and which are the work of cavity formation process and the free energy change due to weak, attractive interactions between the solute molecule and surrounding solvent molecules. We demonstrate that * of the two amphiphilic solutes can be obtained accurately using a perturbation combining method, which relies on the exact expressions for and and requires no simulations of intermediate systems between the solute with strong, repulsive interactions and the solute with the van der Waals and electrostatic interactions.

How do water-mediated interactions and osmotic second virial coefficients vary with particle size?

We examine quantitatively the solute-size dependences of the effective interactions between nonpolar solutes in water and in a simple liquid. The potential () of mean force and the osmotic second virial coefficients are calculated with high accuracy from molecular dynamics simulations. As the solute diameter increases from methane's to C's with the solute-solute and solute-solvent attractive interaction parameters fixed to those for the methane-methane and methane-water interactions, the first minimum of () lowers from -1.

Molecular mechanism of the common and opposing cosolvent effects of fluorinated alcohol and urea on a coiled coil protein.

Alcohols and urea are widely used as effective protein denaturants. Among monohydric alcohols, 2,2,2-trifluoroethanol (TFE) has large cosolvent effects as a helix stabilizer in proteins. In contrast, urea efficiently denatures ordered native structures, including helices, into coils.

Muscarinic acetylcholine receptor-dependent and NMDA receptor-dependent LTP and LTD share the common AMPAR trafficking pathway.

The forebrain cholinergic system promotes higher brain function in part by signaling through the M muscarinic acetylcholine receptor (mAChR). Long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission in the hippocampus are also induced by mAChR. An AMPA receptor (AMPAR) trafficking model for hippocampal neurons has been proposed to simulate N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the early phase.

Immune response to SARS-CoV-2 in severe disease and long COVID-19.

COVID-19 is mild to moderate in otherwise healthy individuals but may nonetheless cause life-threatening disease and/or a wide range of persistent symptoms. The general determinant of disease severity is age mainly because the immune response declines in aging patients. Here, we developed a mathematical model of the immune response to SARS-CoV-2 and revealed that typical age-related risk factors such as only a several 10% decrease in innate immune cell activity and inhibition of type-I interferon signaling by autoantibodies drastically increased the viral load.

Osmotic second virial coefficients for hydrophobic interactions as a function of solute size.

To gain quantitative insight into how the overall strength of the hydrophobic interaction varies with the molecular size, we calculate osmotic second virial coefficients B for hydrophobic spherical molecules of different diameters σ in water based on molecular simulation with corrections to the finite-size and finite-concentration effects. It is shown that B (<0) changes by two orders of magnitude greater as σ increases twofold and its solute-size dependence is best fit by a power law B ∝ σ with the exponent α ≃ 6, which contrasts with the cubic power law that the second virial coefficients of gases obey. It is also found that values of B for the solutes in a nonpolar solvent are positive but they obey the same power law as in water.

Improvement of Protein Solubility in Macromolecular Crowding during Myoglobin Evolution.

The inside of living cells is crowded by extremely high concentrations of biomolecules, and thus globular proteins should have been developed to increase their solubility under such crowding conditions during organic evolution. The O-storage protein myoglobin (Mb) is known to be expressed in myocytes of diving mammals in much larger quantities than those of land mammals. We have previously resurrected ancient whale and pinniped Mbs and experimentally demonstrated that the diving animal Mbs have evolved to maintain high solubility under the crowding conditions or to increase their tolerance against macromolecular precipitants, rather than solubility in a dilute buffer solution.

Kinetics of the ancestral carbon metabolism pathways in deep-branching bacteria and archaea.

The origin of life is believed to be chemoautotrophic, deriving all biomass components from carbon dioxide, and all energy from inorganic redox couples in the environment. The reductive tricarboxylic acid cycle (rTCA) and the Wood-Ljungdahl pathway (WL) have been recognized as the most ancient carbon fixation pathways. The rTCA of the chemolithotrophic Thermosulfidibacter takaii, which was recently demonstrated to take place via an unexpected reverse reaction of citrate synthase, was reproduced using a kinetic network model, and a competition between reductive and oxidative fluxes on rTCA due to an acetyl coenzyme A (ACOA) influx upon acetate uptake was revealed.

Common and unique strategies of myoglobin evolution for deep-sea adaptation of diving mammals.

Myoglobin (Mb) is highly concentrated in the myocytes of diving mammals such as whales and seals, in comparison with land animals, and its molecular evolution has played a crucial role in their deep-sea adaptation. We previously resurrected ancestral whale Mbs and demonstrated the evolutional strategies for higher solubility under macromolecular crowding conditions. Pinnipeds, such as seals and sea lions, are also expert diving mammals with Mb-rich muscles.

Water-mediated interactions destabilize proteins.

Proteins are folded to avoid exposure of the nonpolar groups to water because water-mediated interactions between nonpolar groups are a promising factor in the thermodynamic stabilities of proteins-which is a well-accepted view as one of the unique effects of hydrophobic interactions. This article poses a critical question for this classical view by conducting an accurate solvation free-energy calculation for a thermodynamic cycle of a protein folding using a liquid-state density functional theory. Here, the solvation-free energy for a leucine zipper formation was examined in the coiled-coil protein GCN4-p1, a typical model for hydrophobic interactions, which demonstrated that water-mediated interactions were unfavorable for the association of nonpolar groups in the native state, while the dispersion forces between them were, instead, responsible for the association.

Ion Size Dependences of the Salting-Out Effect: Reversed Order of Sodium and Lithium Ions.

A general trend of the salting-out effect on hydrophobic solutes in aqueous solution is that the smaller the size of a dissolved ion, the larger the effect of reducing the solubility of a hydrophobe. An exception is that Li, the smallest in alkali metal ions, has a notably weaker effect than Na. To understand the reversed order in the cation series, we performed molecular dynamics simulations of aqueous solutions of salt ions and calculated the Setschenow coefficient of methane with the ionic radius of either a cation or an anion varied in a wide range.

Two different regimes in alcohol-induced coil-helix transition: effects of 2,2,2-trifluoroethanol on proteins being either independent of or enhanced by solvent structural fluctuations.

Inhomogeneous distribution of constituent molecules in a mixed solvent has been known to give remarkable effects on the solute, e.g., conformational changes of biomolecules in an alcohol-water mixture.

Unveiling the Interaction Potential Surface between Drug-Entrapped Polymeric Micelles Clarifying the High Drug Nanocarrier Efficiency.

Polymeric micelles are invaluable media as drug nanocarriers. Although knowledge of an interaction between the micelles is a key to understanding the mechanisms and developing the superior functions, the interaction potential surface between drug-incorporated polymeric micelles has not yet been quantitatively evaluated due to the extremely complex structure. Here, the interaction potential surface between drug-entrapped polymeric micelles was unveiled by combining a small-angle scattering experiment and a model-potential-free liquid-state theory.

Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors.

N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and long-term depression (LTD) of signal transmission form neural circuits and thus are thought to underlie learning and memory. These mechanisms are mediated by AMPA receptor (AMPAR) trafficking in postsynaptic neurons. However, the regulatory mechanism of bidirectional plasticity at excitatory synapses remains unclear.

Interaction potential surface between Raman scattering enhancing nanoparticles conjugated with a functional copolymer.

A novel Raman scattering enhancement was discovered using colloid nanoparticles conjugated with an amine-based copolymer. The interaction potential surface between Raman scattering enhancing nanoparticles was clarified by combining a small-angle scattering method and a model-potential-free liquid-state theory as an in situ observation in the solution state. The potential surface indicates that the most stable position is located around 0.

Is F-ATPase a Rotary Motor with Nearly 100% Efficiency? Quantitative Analysis of Chemomechanical Coupling and Mechanical Slip.

We present a chemomechanical network model of the rotary molecular motor F-ATPase which quantitatively describes not only the rotary motor dynamics driven by ATP hydrolysis but also the ATP synthesis caused by forced reverse rotations. We observe a high reversibility of F-ATPase, that is, the main cycle of ATP synthesis corresponds to the reversal of the main cycle in the hydrolysis-driven motor rotation. However, our quantitative analysis indicates that torque-induced mechanical slip without chemomechanical coupling occurs under high external torque and reduces the maximal efficiency of the free energy transduction to 40-80% below the optimal efficiency.

Theoretical analysis on thermodynamic stability of chignolin.

Understanding the dominant factor in thermodynamic stability of proteins remains an open challenge. Kauzmann's hydrophobic interaction hypothesis, which considers hydrophobic interactions between nonpolar groups as the dominant factor, has been widely accepted for about sixty years and attracted many scientists. The hypothesis, however, has not been verified or disproved because it is difficult, both theoretically and experimentally, to quantify the solvent effects on the free energy change in protein folding.

Tracing whale myoglobin evolution by resurrecting ancient proteins.

Extant cetaceans, such as sperm whale, acquired the great ability to dive into the ocean depths during the evolution from their terrestrial ancestor that lived about 50 million years ago. Myoglobin (Mb) is highly concentrated in the myocytes of diving animals, in comparison with those of land animals, and is thought to play a crucial role in their adaptation as the molecular aqualung. Here, we resurrected ancestral whale Mbs, which are from the common ancestor between toothed and baleen whales (Basilosaurus), and from a further common quadrupedal ancestor between whale and hippopotamus (Pakicetus).

Numerical calculation on a two-step subdiffusion behavior of lateral protein movement in plasma membranes.

A two-step subdiffusion behavior of lateral movement of transmembrane proteins in plasma membranes has been observed by using single-molecule experiments. A nested double-compartment model where large compartments are divided into several smaller ones has been proposed in order to explain this observation. These compartments are considered to be delimited by membrane-skeleton "fences" and membrane-protein "pickets" bound to the fences.

Application of reference-modified density functional theory: Temperature and pressure dependences of solvation free energy.

Recently, we proposed a reference-modified density functional theory (RMDFT) to calculate solvation free energy (SFE), in which a hard-sphere fluid was introduced as the reference system instead of an ideal molecular gas. Through the RMDFT, using an optimal diameter for the hard-sphere reference system, the values of the SFE calculated at room temperature and normal pressure were in good agreement with those for more than 500 small organic molecules in water as determined by experiments. In this study, we present an application of the RMDFT for calculating the temperature and pressure dependences of the SFE for solute molecules in water.

Myosin V: Chemomechanical-coupling ratchet with load-induced mechanical slip.

A chemomechanical-network model for myosin V is presented on the basis of both the nucleotide-dependent binding affinity of the head to an actin filament (AF) and asymmetries and similarity relations among the chemical transitions due to an intramolecular strain of the leading and trailing heads. The model allows for branched chemomechanical cycles and takes into account not only two different force-generating mechanical transitions between states wherein the leading head is strongly bound and the trailing head is weakly bound to the AF but also load-induced mechanical-slip transitions between states in which both heads are strongly bound. The latter is supported by the fact that ATP-independent high-speed backward stepping has been observed for myosin V, although such motility has never been for kinesin.

Influence of co-non-solvency on hydrophobic molecules driven by excluded volume effect.

We demonstrate by molecular dynamics simulation that co-non-solvency manifests itself in the solvent-induced interaction between three hydrophobes, methane, propane and neopentane, in methanol-water mixtures. Decomposition of the potential of mean force, based on the potential distribution theorem, clearly shows that the solute-solvent entropic change is responsible for stabilizing the aggregation of these hydrophobic molecules. Furthermore, we show that the entropic change pertains to the excluded volume effect.