Biology subjects

Niina, T.

Publications and source records attributed to Niina, T..

10 recordsLinked to original sources

bioRxiv2026

OpenCafeMol with 3SPN.2 DNA model: GPU Acceleration for Long-Time Coarse-Grained Chromatin Simulations

There is a growing demand for molecular dynamics simulations to explore longer timescale behavior of giant protein-DNA complexes such as chromatin. To address this need, we extended OpenCafeMol, a GPU-accelerated residue-level coarse-grained molecular dynamics simulator originally developed for proteins and lipids, to support 3SPN.2 and 3SPN.2C DNA models. We also implemented a hydrogen-bond-type many-body potential to model DNA-protein interactions more accurately. To further improve computational efficiency, we introduced a localized scheme for calculating base-pairing and cross-stacking interactions. Benchmark tests show that OpenCafeMol on a single GPU achieves up to 200-fold speed-up for DNA-only systems and up to 100-fold speed-up for DNA-protein complexes compared to CPU-based simulations. To demonstrate the capability of our implementation for long-timescale biological processes, we simulated an archaeal SMC-ScpA complex undergoing DNA translocation via segment capture (a proposed mechanism for DNA loop extrusion) in the presence of a DNA-bound obstacle. We observed continuous captured-loop growth accompanied by obstacle bypass within the segment capture framework.

biophysics↗

bioRxiv2025

OpenCafeMol: A GPU-accelerated coarse-grained biomoleculardynamics simulator with OpenMM library

There has been an increasing demand for longer-timescale molecular dynamics (MD) simulations of larger biomolecular systems. To meet these demands, using the C++ API of OpenMM, we developed a fast and flexible MD software, OpenCafeMol, for residue-resolution protein and lipid models that shows high performance on graphics processing unit (GPU) machines. We validated OpenCafeMol for folding small proteins, lipid membrane dynamics, and membrane protein structures. Benchmark tests of the computation times showed that OpenCafeMol with one GPU for proteins and lipid membranes can be approximately 100 and 240 times faster than the corresponding simulations on a typical CPU machine (eight cores), respectively. Taking advantage of the high speed of OpenCafeMol, we applied it to two sets of vesicle fusion simulations; one driven by force and the other coupled with conformational dynamics of a SNARE complex. In the latter, a direct MD simulation at a high temperature resulted in vesicle docking, pore formation followed by fusion, which are coupled with local folding of linkers in the SNARE complex. This opens up new avenue to study membrane-fusion mechanisms via MD simulations. The source code for OpenCafeMol is fully available.

biophysics↗

bioRxiv2022

The stoichiometric interaction model for mesoscopic molecular dynamics 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 case in which condensates are formed by multivalent proteins with tandem domains. One problem with this approach is that interdomain pairwise interactions cannot regulate the valency of the binding domains. To overcome this problem, we propose a new potential, the stoichiometric interaction (SI) potential. First, we verified that the SI potential maintained the valency of the interacting domains for the test systems. We then examined a well-studied LLPS model system containing tandem repeats of SH3 domains and proline-rich motifs. We found that the SI potential alone cannot reproduce the phase diagram of LLPS quantitatively. We had to combine the SI and a pairwise interaction; the former and the latter represent the specific and non-specific interactions, respectively. Biomolecular condensates with the mixed SI and pairwise interaction exhibited fluidity, whereas those with the pairwise interaction alone showed no detectable diffusion. We also compared the phase diagrams of the systems containing different numbers of tandem domains with those obtained from the experiments, and found quantitative agreement in all but one case. SIGNIFICANCECells organize their interior structures as not only membrane-bound organelles but also as membrane-less organelles. Membrane-less organelles, such as stress granules, Cajal bodies, and postsynaptic density, are biomolecular condensates in which many biomolecules are gathered owing to their interactions. In some cases, biomolecular condensates are formed by tandemly connected multidomain proteins. In such cases, a mesoscopic simulation model representing each domain as a particle is effective; however, the problem with this approach is that a domain-domain pairwise interaction cannot regulate the well-defined valency. To overcome this problem, in this study, we have developed a new potential, viz. the stoichiometric interaction potential, and confirmed that this potential can reproduce the liquid-liquid phase separation of multidomain proteins, a hallmark of the membrane-less organelles.

biophysics↗

bioRxiv2021

F0-F1 coupling and symmetry mismatch in ATP synthase resolved in every F0 rotation step

The F0F1 ATP synthase, essential for cellular energy production, is composed of the F0 and F1 rotary motors. While both F0 and F1 have pseudo-symmetric structures, their symmetries do not match. How the symmetry mismatch is solved remains elusive due to missing intermediate structures of rotational steps. Here, for ATP synthases with 3- and 10-fold symmetries in F1 and F0, respectively, we uncovered the mechanical couplings between F0 and F1 at every 36{degrees} rotation step via molecular dynamics simulations and comparison of cryo-electron microscopy structures from three species. We found that the frustration is shared by several elements. The F1 stator partially rotates relative to the F0 stator via elastic distortion of the b-subunits. The rotor can be distorted. The c-ring rotary angles can be deviated from symmetric ones. Additionally, the F1 motor may take non-canonical structures relieving stronger frustration. Together, we provide comprehensive understanding to solve the symmetry mismatch.

biophysics↗

bioRxiv2021

Cooperation among c-subunits of FoF1-ATP synthase in rotation-coupled proton translocation

In FoF1-ATP synthase, proton translocation through Fo drives rotation of the c-subunit oligomeric ring relative to the a-subunit. Recent studies suggest that in each step of the rotation, key glutamic acid residues in different c-subunits contribute to proton release to and proton uptake from the a-subunit. However, no studies have demonstrated cooperativity among c-subunits toward FoF1-ATP synthase activity. Here, we addressed this using Bacillus PS3 ATP synthase harboring c-ring with various combinations of wild-type and cE56D, enabled by genetically fused single-chain c-ring. ATP synthesis and proton pump activities were decreased by a single cE56D mutation and further decreased by double cE56D mutations. Moreover, activity further decreased as the two mutation sites were separated, indicating cooperation among c-subunits. Similar results were obtained for proton transfer-coupled molecular simulations. Simulations revealed that prolonged proton uptake in mutated c-subunits is shared between two c-subunits, explaining the cooperation observed in biochemical assays.

biochemistry↗

bioRxiv2021

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. First, we examined four similarity scores via twin-experiments for four test proteins, finding that the cosine similarity score generally worked best, whereas the pixel-RMSD and the correlation coefficient were also useful. We then applied the method to two experimental high-speed-AFM images inferring the probe shape and the molecular placement. The results suggest that the appropriate similarity score can differ between target systems. For an actin filament image, the cosine similarity apparently worked best. For an image of the flagellar protein FlhAC, we found the correlation coefficient gave better results. This difference may partly be attributed to the flexibility in the target molecule, ignored in the rigid-body fitting. The inferred tip shape and placement results can be further refined by other methods, such as the flexible fitting molecular dynamics simulations. The developed software is publicly available. Author SummaryObservation of functional dynamics of individual biomolecules is important to understand molecular mechanisms of cellular phenomena. High-speed (HS) atomic force microscopy (AFM) is a powerful tool that enables us to visualize the real-time dynamics of working biomolecules under near-physiological conditions. However, the information available by the AFM images is limited to the two-dimensional surface shape detected via the force to the probe. While the surface information is affected by the shape of the probe tip, the probe shape itself cannot be directly measured before each AFM measurement. To overcome this problem, we have developed a computational method to simultaneously infer the probe tip shape and the molecular placement from an AFM image. We show that our method successfully estimates the effective AFM tip shape and visualizes a structure with a more accurate placement. The estimation of a molecular placement with the correct probe tip shape enables us to obtain more insights into functional dynamics of the molecule from HS-AFM images.

biophysics↗

bioRxiv2020

The Particle Filter Method to Integrate High-Speed Atomic Force Microscopy Measurement with Biomolecular Simulations

The high-speed atomic force microscopy (HS-AFM) can observe structural dynamics of biomolecules at single-molecule level in real time near physiological condition, but its spatiotemporal resolution is limited. Complementarily, molecular dynamics (MD) simulations have higher spatiotemporal resolutions albeit with some artifact. Here, in order to integrate the HS-AFM data and coarse-grained (CG)-MD simulations, we develop a particle filter method, one of the sequential Bayesian data assimilation approaches. We tested the method in a twin experiment. We first made a reference HS-AFM movie from a CG-MD trajectory of a test molecule, a nucleosome, which serves as an "experimental measurement". Then, we performed the particle filter simulation with 512 particles that captured large-scale nucleosome structural dynamics compatible with the AFM movie. Comparing the particle filter simulations with 8 - 8192 particles, we found that the use of more particles consistently results in larger likelihood for the whole AFM movie. By comparing the likelihoods from different ionic concentrations and from different timescales, we found that the "true" concentration and timescale can be inferred as the largest likelihood of the whole AFM movie, but not that of each AFM image. The particle filter method provides a general approach to integrate the HS-AFM data with MD simulations.

biophysics↗

bioRxiv2019

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

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 biomolecular structure into an AFM image. First, we describe a method to produce a pseudo-AFM image from a given three-dimensional structure in a differentiable form. Then, using a correlation function between the experimental AFM image and the computational pseudo-AFM image, we developed a flexible fitting molecular dynamics (MD) simulation method, by which we obtain protein structures that well fit to the given AFM image. We first test it with a twin-experiment; for a synthetic AFM image produced from a protein structure different from its native conformation, the flexible fitting MD simulations sampled those that fit well the AFM image. Then, parameter dependence in the protocol is discussed. Finally, we applied the method to a real experimental AFM image for a flagellar protein FlhA, demonstrating its applicability. We also test the rigid-body fitting of a fixed structure to the AFM image. Our method will be a general tool for structure modeling based on AFM images and is publicly available through CafeMol software.

biophysics↗

bioRxiv2019

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

The FO motor in FOF1 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 FO rotary dynamics at structural details. Here, developing a hybrid Monte Carlo/molecular dynamics simulation method, we studied reversible dynamics of a yeast mitochondrial FO. We obtained the 36{degrees}-stepwise rotations of FO per one proton transfer in the ATP synthesis mode and the proton pumping in the ATP hydrolysis mode. In both modes, the most prominent path alternatively sampled states with two and three deprotonated glutamates in c-ring, by which the c-ring rotates one step. The free energy transduction efficiency in the model FO motor reaches ~ 90% in optimal conditions. Moreover, mutations in key glutamate and a highly conserved arginine increased proton leakage and markedly decreased the coupling, in harmony with previous experiments.

biophysics↗

bioRxiv2017

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. A uniform DNA sequence showed frequent sliding with one base pair step in a rotation-coupled manner, akin to screw-like motions. On the contrary, a strong positioning sequence, the so-called 601 sequence, exhibits rare, abrupt transitions of five and ten base pair steps without rotation. Moreover, we evaluated the importance of hydrogen bond interactions on the sliding mode, finding that strong and weak bonds favor respectively the rotation-coupled and -uncoupled sliding movements.\n\nAuthor summaryNucleosomes are fundamental units of chromatin folding consisting of double-stranded DNA wrapped [~]1.7 times around a histone octamer. By densely populating the eukaryotic genome, nucleosomes enable efficient genome compaction inside the cellular nucleus. However, the portion of DNA occupied by a nucleosome can hardly be accessed by other DNA-binding proteins, obstructing fundamental cellular processes such as DNA replication and transcription. DNA compaction and access by other proteins can simultaneously be achieved via the dynamical repositioning of nucleosomes, which can slide along the DNA sequence. In this study, we developed and used coarse-grained molecular dynamics simulations to reveal the molecular details of nucleosome sliding. We find that the sliding mode is highly dependent on the underlying DNA sequence. Specifically, a sequence with a strong nucleosome positioning signal slides via large jumps by five and ten base pairs, preserving the optimal DNA bending profile. On the other hand, uniform sequences without the positioning signal slide via a screw-like motion of DNA, one base pair at the time. These results show that sequence has a large effect not only on the formation of nucleosomes, but also on the kinetics of repositioning.

biophysics↗