Theoretical insights into rotary mechanism of MotAB in the bacterial flagellar motor.

Many bacteria enable locomotion by rotating their flagellum. It has been suggested that this rotation is realized by the rotary motion of the stator unit, MotAB, which is driven by proton transfer across the membrane. Recent cryo-electron microscopy studies have revealed a 5:2 MotAB configuration, in which a MotB dimer is encircled by a ring-shaped MotA pentamer.

Multiscale Bayesian simulations reveal functional chromatin condensation of gene loci.

Chromatin, the complex assembly of DNA and associated proteins, plays a pivotal role in orchestrating various genomic functions. To aid our understanding of the principles underlying chromatin organization, we introduce Hi-C metainference, a Bayesian approach that integrates Hi-C contact frequencies into multiscale prior models of chromatin. This approach combines both bottom-up (the physics-based prior) and top-down (the data-driven posterior) strategies to characterize the 3D organization of a target genomic locus.

Extension of the iSoLF implicit-solvent coarse-grained model for multicomponent lipid bilayers.

iSoLF is a coarse-grained (CG) model for lipid molecules with the implicit-solvent approximation used in molecular dynamics (MD) simulations of biological membranes. Using the original iSoLF (iSoLFv1), MD simulations of lipid bilayers consisting of either POPC or DPPC and these bilayers, including membrane proteins, can be performed. Here, we improve the original model, explicitly treating the electrostatic interactions between different lipid molecules and adding CG particle types.

Postsynaptic protein assembly in three and two dimensions studied by mesoscopic simulations.

Recently, cellular biomolecular condensates formed via phase separation have received considerable attention. While they can be formed either in cytosol (denoted as 3D) or beneath the membrane (2D), the underlying difference between the two has not been well clarified. To compare the phase behaviors in 3D and 2D, postsynaptic density (PSD) serves as a model system.

Micelle-like clusters in phase-separated Nanog condensates: A molecular simulation study.

The phase separation model for transcription suggests that transcription factors (TFs), coactivators, and RNA polymerases form biomolecular condensates around active gene loci and regulate transcription. However, the structural details of condensates remain elusive. In this study, for Nanog, a master TF in mammalian embryonic stem cells known to form protein condensates in vitro, we examined protein structures in the condensates using residue-level coarse-grained molecular simulations.

Removing the parachuting artifact using two-way scanning data in high-speed atomic force microscopy.

The high-speed atomic force microscopy (HS-AFM) is a unique and prominent method to observe structural dynamics of biomolecules at single molecule level at near-physiological condition. To achieve high temporal resolution, the probe tip scans the stage at high speed which can cause the so-called parachuting artifact in the HS-AFM images. Here, we develop a computational method to detect and remove the parachuting artifact in HS-AFM images using the two-way scanning data.

Histone chaperone Nap1 dismantles an H2A/H2B dimer from a partially unwrapped nucleosome.

DNA translocases, such as RNA polymerases, inevitably collide with nucleosomes on eukaryotic chromatin. Upon these collisions, histone chaperones are suggested to facilitate nucleosome disassembly and re-assembly. In this study, by performing in vitro transcription assays and molecular simulations, we found that partial unwrapping of a nucleosome by an RNA polymerase dramatically facilitates an H2A/H2B dimer dismantling from the nucleosome by Nucleosome Assembly Protein 1 (Nap1).

Particle Smoother to Assimilate Asynchronous Movie Data of High-Speed AFM with MD Simulations.

High-speed (HS) atomic force microscopy (AFM) can be used to observe structural dynamics of biomolecules under near-physiological conditions. In the AFM measurement, the probe tip scans an area of interest and acquires height data pixel by pixel so that the obtained AFM image contains a measurement time difference. In this study, to integrate molecular dynamics simulations with asynchronous HS-AFM movie data, we developed a particle smoother (PS) method for Bayesian data assimilation, one of the machine learning approaches, by extending the previous particle filter method.

End-to-end differentiable blind tip reconstruction for noisy atomic force microscopy images.

Observing the structural dynamics of biomolecules is vital to deepening our understanding of biomolecular functions. High-speed (HS) atomic force microscopy (AFM) is a powerful method to measure biomolecular behavior at near physiological conditions. In the AFM, measured image profiles on a molecular surface are distorted by the tip shape through the interactions between the tip and molecule.

Molecular dynamics simulations for the study of chromatin biology.

The organization of Eukaryotic DNA into chromatin has profound implications for the processing of genetic information. In the past years, molecular dynamics (MD) simulations proved to be a powerful tool to investigate the mechanistic basis of chromatin biology. We review recent all-atom and coarse-grained MD studies revealing how the structure and dynamics of chromatin underlie its biological functions.

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.

Coarse-grained molecular dynamics simulations of base-pair mismatch recognition protein MutS sliding along DNA.

DNA mismatches are frequently generated by various intrinsic and extrinsic factors including DNA replication errors, oxygen species, ultraviolet, and ionizing radiation. These mismatches should be corrected by the mismatches repair (MMR) pathway to maintain genome integrity. In the () MMR pathway, MutS searches and recognizes a base-pair mismatch from millions of base-pairs.

Rotational Mechanism of F Motor in the F-Type ATP Synthase Driven by the Proton Motive Force.

In FF ATP synthase, driven by the proton motive force across the membrane, the F motor rotates the central rotor and induces conformational changes in the F motor, resulting in ATP synthesis. Recently, many near-atomic resolution structural models have been obtained using cryo-electron microscopy. Despite high resolution, however, static information alone cannot elucidate how and where the protons pass through the F and how proton passage is coupled to F rotation.

Inferring Conformational State of Myosin Motor in an Atomic Force Microscopy Image Flexible Fitting Molecular Simulations.

High-speed atomic force microscopy (HS-AFM) is a powerful technique to image the structural dynamics of biomolecules. We can obtain atomic-resolution structural information from the measured AFM image by superimposing a structural model on the image. We previously developed a flexible fitting molecular dynamics (MD) simulation method that allows for modest conformational changes when superimposed on an AFM image.

Implementation of residue-level coarse-grained models in GENESIS for large-scale molecular dynamics simulations.

Residue-level coarse-grained (CG) models have become one of the most popular tools in biomolecular simulations in the trade-off between modeling accuracy and computational efficiency. To investigate large-scale biological phenomena in molecular dynamics (MD) simulations with CG models, unified treatments of proteins and nucleic acids, as well as efficient parallel computations, are indispensable. In the GENESIS MD software, we implement several residue-level CG models, covering structure-based and context-based potentials for both well-folded biomolecules and intrinsically disordered regions.

Corrigendum: Modeling DNA Opening in the Eukaryotic Transcription Initiation Complexes Coarse-Grained Models.

[This corrects the article DOI: 10.3389/fmolb.2021.

Modeling DNA Opening in the Eukaryotic Transcription Initiation Complexes via Coarse-Grained Models.

Recently, the molecular mechanisms of transcription initiation have been intensively studied. Especially, the cryo-electron microscopy revealed atomic structure details in key states in the eukaryotic transcription initiation. Yet, the dynamic processes of the promoter DNA opening in the pre-initiation complex remain obscured.

Modeling lipid-protein interactions for coarse-grained lipid and Cα protein models.

Biological membranes that play major roles in diverse functions are composed of numerous lipids and proteins, making them an important target for coarse-grained (CG) molecular dynamics (MD) simulations. Recently, we have developed the CG implicit solvent lipid force field (iSoLF) that has a resolution compatible with the widely used Cα protein representation [D. Ugarte La Torre and S.

The lane-switch mechanism for nucleosome repositioning by DNA translocase.

Translocases such as DNA/RNA polymerases, replicative helicases, and exonucleases are involved in eukaryotic DNA transcription, replication, and repair. Since eukaryotic genomic DNA wraps around histone octamers and forms nucleosomes, translocases inevitably encounter nucleosomes. A previous study has shown that a nucleosome repositions downstream when a translocase collides with the nucleosome.

Testing mechanisms of DNA sliding by architectural DNA-binding proteins: dynamics of single wild-type and mutant protein molecules in vitro and in vivo.

Architectural DNA-binding proteins (ADBPs) are abundant constituents of eukaryotic or bacterial chromosomes that bind DNA promiscuously and function in diverse DNA reactions. They generate large conformational changes in DNA upon binding yet can slide along DNA when searching for functional binding sites. Here we investigate the mechanism by which ADBPs diffuse on DNA by single-molecule analyses of mutant proteins rationally chosen to distinguish between rotation-coupled diffusion and DNA surface sliding after transient unbinding from the groove(s).

Semi-Implicit Time Integration with Hessian Eigenvalue Corrections for a Larger Time Step in Molecular Dynamics Simulations.

In molecular dynamics simulations, the limited time step size has been a barrier to simulating long-time behaviors. Implicit time integration methods allow markedly larger time steps than the standard explicit time method, although they have major drawbacks such as overheads solving linear systems and instability of Newton iterations. To overcome these issues, we propose a semi-implicit time integration scheme, the semi-implicit Hessian correction (SimHec) scheme, for overdamped Langevin dynamics.

Modeling of DNA binding to the condensin hinge domain using molecular dynamics simulations guided by atomic force microscopy.

The condensin protein complex compacts chromatin during mitosis using its DNA-loop extrusion activity. Previous studies proposed scrunching and loop-capture models as molecular mechanisms for the loop extrusion process, both of which assume the binding of double-strand (ds) DNA to the hinge domain formed at the interface of the condensin subunits Smc2 and Smc4. However, how the hinge domain contacts dsDNA has remained unknown.