The stoichiometric interaction model for mesoscopic MD simulations of liquid-liquid phase separation.

Liquid-liquid phase separation (LLPS) has received considerable attention in recent years for explaining the formation of cellular biomolecular condensates. The fluidity and the complexity of their components make molecular simulation approaches indispensable for gaining structural insights. Domain-resolution mesoscopic model simulations have been explored for cases in which condensates are formed by multivalent proteins with tandem domains.

F-F coupling and symmetry mismatch in ATP synthase resolved in every F rotation step.

FF ATP synthase, a ubiquitous enzyme that synthesizes most ATP in living cells, is composed of two rotary motors: a membrane-embedded proton-driven F motor and a catalytic F motor. These motors share both central and peripheral stalks. Although both F and F have pseudo-symmetric structures, their symmetries do not match.

Rigid-body fitting to atomic force microscopy images for inferring probe shape and biomolecular structure.

Atomic force microscopy (AFM) can visualize functional biomolecules near the physiological condition, but the observed data are limited to the surface height of specimens. Since the AFM images highly depend on the probe tip shape, for successful inference of molecular structures from the measurement, the knowledge of the probe shape is required, but is often missing. Here, we developed a method of the rigid-body fitting to AFM images, which simultaneously finds the shape of the probe tip and the placement of the molecular structure via an exhaustive search.

Case Report: Bayesian Statistical Inference of Experimental Parameters via Biomolecular Simulations: Atomic Force Microscopy.

The atomic force microscopy (AFM) is a powerful tool for imaging structures of molecules bound on surfaces. To gain high-resolution structural information, one often superimposes structure models on the measured images. Motivated by high flexibility of biomolecules, we previously developed a flexible-fitting molecular dynamics (MD) method that allows protein structural changes upon superimposing.

Particle Filter Method to Integrate High-Speed Atomic Force Microscopy Measurements with Biomolecular Simulations.

High-speed atomic force microscopy (HS-AFM) can be used to observe the structural dynamics of biomolecules at the single-molecule level in real time under near-physiological conditions; however, its spatiotemporal resolution is limited. Complementarily, molecular dynamics (MD) simulations have higher spatiotemporal resolutions, albeit with some artifacts. Here, to integrate HS-AFM data and coarse-grained molecular dynamics (CG-MD) simulations, we develop a particle filter method that implements a sequential Bayesian data assimilation approach.

Molecular dynamics simulation of proton-transfer coupled rotations in ATP synthase F motor.

The F motor in FF ATP synthase rotates its rotor driven by the proton motive force. While earlier studies elucidated basic mechanisms therein, recent advances in high-resolution cryo-electron microscopy enabled to investigate proton-transfer coupled F rotary dynamics at structural details. Here, taking a hybrid Monte Carlo/molecular dynamics simulation method, we studied reversible dynamics of a yeast mitochondrial F.

Flexible Fitting of Biomolecular Structures to Atomic Force Microscopy Images via Biased Molecular Simulations.

High-speed (HS) atomic force microscopy (AFM) is a prominent imaging technology that observes large-scale structural dynamics of biomolecules near the physiological condition, but the AFM data are limited to the surface shape of specimens. Rigid-body fitting methods were developed to obtain molecular structures that fit to an AFM image, without accounting for conformational changes. Here, we developed a method to fit flexibly a three-dimensional (3D) biomolecular structure into an AFM image.

DNA sliding in nucleosomes via twist defect propagation revealed by molecular simulations.

While nucleosomes are highly stable structures as fundamental units of chromatin, they also slide along the DNA, either spontaneously or by active remodelers. Here, we investigate the microscopic mechanisms of nucleosome sliding by multiscale molecular simulations, characterizing how the screw-like motion of DNA proceeds via the formation and propagation of twist defects. Firstly, coarse-grained molecular simulations reveal that the sliding dynamics is highly dependent on DNA sequence.

Sequence-dependent nucleosome sliding in rotation-coupled and uncoupled modes revealed by molecular simulations.

While nucleosome positioning on eukaryotic genome play important roles for genetic regulation, molecular mechanisms of nucleosome positioning and sliding along DNA are not well understood. Here we investigated thermally-activated spontaneous nucleosome sliding mechanisms developing and applying a coarse-grained molecular simulation method that incorporates both long-range electrostatic and short-range hydrogen-bond interactions between histone octamer and DNA. The simulations revealed two distinct sliding modes depending on the nucleosomal DNA sequence.