Shigetaka Yoneda

The structure of heterotetrameric sarcosine oxidase (HSO) contains a highly complex system composed of a large cavity and tunnels, which are essential for the reaction and migration of the reactants, products, and intermediates. Previous geometrical analysis using the CAVER program has predicted that there are three possible tunnels, T1, T2, and T3, for the exit pathway of the iminium intermediate, 5‐oxazolidinone (5‐OXA), of the enzyme reaction. Previous molecular dynamics (MD) simulation of HSO has identified the regions containing the water channels from the density distribution of water. The simulation indicated that tunnel T3 is the most probable exit pathway of 5‐OXA. In the present study, the potential of mean force (PMF) for the transport of 5‐OXA through tunnels T1, T2, and T3 was calculated using umbrella sampling (US) MD simulations and the weighted histogram analysis method. The PMF profiles for the three tunnels support the notion that tunnel T3 is the exit pathway of 5‐OXA, and that 5‐OXA tends to stay at the middle of the tunnel. The maximum errors of the calculated PMF for the predicted exit pathway, tunnel T3, were estimated by repeating the US simulations using different sets of initial positions. The PMF profile was also calculated for the transport of glycine within T3. The PMF profiles from the US simulations were in good agreement with the previous predictions that 5‐OXA escape through tunnel T3 and how glycine is released to the outside of HSO was discussed.

The structure of heterotetrameric sarcosine oxidase (HSO) contains a highly complex system composed of a large cavity and tunnels, which are essential for the reaction and migration of the reactants, products, and intermediates. Previous molecular dynamics (MD) simulation of HSO has identified the regions containing the water channels from the density distribution of water. The simulation is consistent with the selective transport hypothesis of the migration of the iminium intermediate, 5-oxazolidinone (5-OXA), of the enzyme reaction whereby tunnel T3 is the exit pathway of 5-OXA. In the present study, the potential of mean force (PMF) for the transport of 5-OXA through tunnels T1, T2, and T3 was calculated using umbrella sampling (US) MD simulations and the weighted histogram analysis method. The maximum errors of the calculated PMF were estimated by repeating the US simulations using different sets of initial positions. The PMF profiles for the three tunnels support the notion that tunnel T3 is the exit pathway of 5-OXA and that 5-OXA tends to stay at the middle of the tunnel. The PMF profile for the transport of glycine through tunnel T3 was also calculated to investigate where 5-OXA is converted into glycine, and how glycine is released to the outside of HSO was explained.

Nematic liquid crystals (N-LCs) are known to transform into chiral nematic liquid crystals (N*-LCs) with helical structures upon doping with enantiomeric compounds (chiral dopants or guests). Here, we investigated the mechanism of host LC- and guest-dependent helix inversion by using octahedral metal complexes as guests. The helical twisting powers (HTPs /μm-1) of eight metal complexes with ΔΛ chirality were examined in five nematic LC hosts. For example, Δ-[Ru(acac)₂(trop)] (Ru-trop, Hacac=2,4-pentanedione, Htrop=tropolone) induces a left-handed (M) helix upon doping with N-(4-methoxybenzylidene)-4-butylaniline (MBBA), whereas it induces an opposite right-handed (P) helix in 4-cyano-4'-pentylbiphenyl (5CB). Further, the monobrominated complex of Ru-trop, Δ-[Ru(acac)2(Brtrop)] (Ru-Br₁trop, HBr₁trop = 5-bromotropolone), induces P helices in both MBBA and 5CB, while the dibrominated complex, Δ-[Ru(acac)₂(Br₂trop)] (Ru-Br₂trop, HBr₂trop=3,7-dibromotroplone) induces M helices in both the media. Molecular dynamics simulation performed in parallel confirmed the drastic effect of the bromo group in guest complexes on the microscopic ordering direction of them in nematics. Further, HTPs of all Δ isomers of metal complexes investigated were found to shift in the positive direction as the dielectric constant anisotropy (Δε) of the host LCs increases (and vice versa for Λ isomers). These experimental and calculated results highlight the interplay of steric (exclusive volume effect) and electrostatic (dipole-dielectric body) interactions between the host LCs and guest metal complexes.

A new program library named “CAPLIB” was developed for the modeling and analysis of icosahedrally symmetric virus capsids. CAPLIB is equipped with the mathematical data of 60 rotation matrices of icosahedral symmetry, 15 planes bisecting the entire capsid structure, and a table summarizing how the 60 asymmetric units (cells) are partitioned by the planes. CAPLIB contains the function to determine the cell numbers of atoms from the atomic positions and the function to determine the rotation axes and angles from the rotation matrices. Using CAPLIB, it is possible to generate the structure of any selected protein unit within the entire capsid by rotating a single protein unit structure. CAPLIB can classify Protein Data Bank files of capsids with the directions of rotation axes, rotate the protein structure onto the standard position, and perform various deformations of the entire capsid. The interface to the molecular graphics software, PyMOL, was also developed for efficient modeling of capsids.

Hepatitis B virus (HBV) chronically infects millions of people worldwide and is a major cause of serious liver diseases, including liver cirrhosis and liver cancer. In our previous study, in silico screening was used to isolate new anti-viral compounds predicted to bind to the HBV capsid. Four of the isolated compounds have been reported to suppress the cellular multiplication of HBV experimentally. In the present study, molecular dynamics simulations of the HBV capsid were performed under rotational symmetry boundary conditions, to clarify how the structure and dynamics of the capsid are affected at the atomic level by the binding of one of the isolated compounds, C13. Two simulations of the free HBV capsid, two further simulations of the capsid-C13 complex, and one simulation of the capsid-AT-130 complex were performed. For statistical confidence, each set of simulations was repeated by five times, changing the simulation conditions. C13 continued to bind at the predicted binding site during the simulations, supporting the hypothesis that C13 is a capsid-binding compound. The structure and dynamics of the HBV capsid were greatly influenced by the binding and release of C13, and these effects were essentially identical to those seen for AT-130, indicating that C13 likely inhibits the function of the HBV capsid.

A precise 100-ns molecular dynamics simulation in aquo was performed for the heterotetrameric sarcosine oxidase bound with a substrate analogue, dimethylglycine. The spatial region including the protein was divided into small rectangular cells. The average number of the water molecules locating within each cell was calculated based on the simulation trajectory. The clusters of the cells filled with water molecules were used to determine the water channels. The narrowness of the channels, the average hydropathy indices of the residues of the channels, and the number of migration events of water molecules through the channels were consistent with the selective transport hypothesis whereby tunnel T3 is the pathway for the exit of the iminium intermediate of the enzyme reaction.

Fourier analysis, using the atomic trajectory calculated by molecular dynamics simulation at 300 K, is applied to the study of low-frequency phonons of guanine dihydrate. The vibrational modes of guanine bases are analyzed, and the optically active modes associated with the guanine moieties are extracted. There are a few significant peaks in the low-frequency region. A possible assignment of the Raman active mode near 27 cm^-1, whose origin would be common to the S-mode of DNA double helices, is discussed.