Drug binding dynamics of the dimeric SARS-CoV-2 main protease, determined by molecular dynamics simulation.

We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein-ligand complexes and suggest the possibilities of further drug optimisations.

All-Atom Molecular Dynamics Simulations of Entire Virus Capsid Reveal the Role of Ion Distribution in Capsid's Stability.

Present experimental methods do not have sufficient resolution to investigate all processes in virus particles at atomistic details. We report the results of molecular dynamics simulations and analyze the connection between the number of ions inside an empty capsid of PCV2 virus and its stability. We compare the crystallographic structures of the capsids with unresolved N-termini and without them in realistic conditions (room temperature and aqueous solution) and show that the structure is preserved. We find that the chloride ions play a key role in the stability of the capsid. A low number of chloride ions results in loss of the native icosahedral symmetry, while an optimal number of chloride ions create a neutralizing layer next to the positively charged inner surface of the capsid. Understanding the dependence of the capsid stability on the distribution of the ions will help clarify the details of the viral life cycle that is ultimately connected to the role of packaged viral genome inside the capsid.

Thermal transistor utilizing gas-liquid transition.

We propose a simple thermal transistor, a device to control heat current. In order to effectively change the current, we utilize the gas-liquid transition of the heat-conducting medium (fluid) because the gas region can act as a good thermal insulator. The three terminals of the transistor are located at both ends and the center of the system, and are put into contact with distinct heat baths. The key idea is a special arrangement of the three terminals. The temperature at one end (the gate temperature) is used as an input signal to control the heat current between the center (source, hot) and another end (drain, cold). Simulating the nanoscale systems of this transistor, control of heat current is demonstrated. The heat current is effectively cut off when the gate temperature is cold and it flows normally when it is hot. By using an extended version of this transistor, we also simulate a primitive application for an inverter.

Thermal diode utilizing asymmetric contacts to heat baths.

We propose a simple thermal diode passively acting as a rectifier of heat current. The key design of the diode is the size asymmetry of the areas in contact with two distinct heat baths. The heat-conducting medium is liquid, inside of which gaslike regions are induced depending on the applied conditions. Simulating nanoscale systems of this diode, the rectification of heat current is demonstrated. If the packing density of the medium and the working regime of temperature are properly chosen, the heat current is effectively cut off when the heat bath with narrow contact is hotter, but it flows normally under opposite temperature conditions. In the former case, the gaslike region is induced in the system and it acts as a thermal insulator because it covers the entire narrow area of contact with the bath.

Steady-state thermodynamics for heat conduction: microscopic derivation.

Starting from microscopic mechanics, we derive thermodynamic relations for heat conducting nonequilibrium steady states. The extended Clausius relation enables one to experimentally determine nonequilibrium entropy to the second order in the heat current. The associated Shannon-like microscopic expression of the entropy is suggestive. When the heat current is fixed, the extended Gibbs relation provides a unified treatment of thermodynamic forces in the linear nonequilibrium regime.

Expression for the stationary distribution in nonequilibrium steady states.

We study the nonequilibrium steady state realized in a general stochastic system attached to multiple heat baths. Starting from the detailed fluctuation theorem, we derive concise and suggestive expressions for the corresponding stationary distribution which are correct up to the second order in thermodynamic forces. The probability of a microstate eta is proportional to exp[Phi(eta)] where Phi(eta)=-[under summation operator]kbeta_{k}E_{k}(eta) is the excess entropy change. Here, E_{k}(eta) is the difference between two kinds of conditioned path ensemble averages of excess heat transfer from the kth heat bath whose inverse temperature is beta_{k}. This result can be easily extended to steady states maintained with other sources, e.g., particle current driven by an external force. Our expression may be verified experimentally in nonequilibrium states realized, for example, in mesoscopic systems.

Hidden heat transfer in equilibrium states implies directed motion in nonequilibrium states.

We study a class of heat engines including Feynman's ratchet, which exhibits a directed motion of a particle in nonequilibrium steady states maintained by two heat baths. We measure heat transfer from each heat bath separately, and average them using a careful procedure that reveals the nature of the heat transfer associated with directed steps of the particle. Remarkably we find that steps are associated with nonvanishing heat transfer even in equilibrium, and there is a quantitative relation between this hidden heat transfer and the directed motion of the particle. This relation is clearly understood in terms of the principle of heat transfer enhancement, which is expected to apply to a large class of highly nonequilibrium systems.

Energy conversion by autonomous regulation of chaos: dynamical mechanism of loose coupling.

Inspired by recent experiments of molecular motors, a dynamical systems model for a flexible machine is proposed which converts injected energy to output directional motion. The output amount is distributed broadly, and thus the coupling between input energy and output motion is loose, as in the experiments. This energy conversion is shown to be robust against the change of surrounding environment. Stability analysis on the fixed point solutions of the model is presented, which suggests that transient chaotic motion, induced by temporal three-body motion, is relevant to the energy conversion.