Publications by authors named "Yuichi Togashi"
Article Synopsis
- The adaptive biasing force (ABF) technique helps maintain a uniform free energy landscape during molecular dynamics (MD) simulations, allowing for more accurate results in complex interactions.
- The paper outlines a detailed protocol for conducting MD simulations using ABF, focusing on calculating the binding free energy of RNA:RNA interactions.
- Key aspects include server setup, software testing, model building, and running ABF-MD simulations, as well as tips for analyzing the resulting binding free energy and structural changes.
Periodic boundary conditions are commonly applied in molecular dynamics simulations in the microcanonical (NVE), canonical (NVT), and isothermal-isobaric (NpT) ensembles. In their simplest application, a biological system of interest is placed in the middle of a solvation box, which is chosen 'sufficiently large' to minimize any numerical artifacts associated with the periodic boundary conditions. This practical approach brings limitations to the size of biological systems that can be simulated.
View Article and Find Full Text PDFMolecular dynamics analysis of biomolecular systems including nucleic acids.
Biophys Physicobiol
August 2022
Article Synopsis
- Recent advances in structural and genome biology have increased interest in the structural dynamics of nucleic acids, particularly regarding gene regulation.
- Understanding the structure-function relationship highlights the importance of the properties of nucleotides and amino acids in proteins.
- Although molecular simulations are useful for studying molecular dynamics, the field of nucleic acid simulation is less advanced than that of proteins, which prompts a call for collaboration between experimentalists and computational biologists.
In contrast to prokaryotes wherein GUG and UUG are permissive start codons, initiation frequencies from non-AUG codons are generally low in eukaryotes, with CUG being considered as strongest. Here, we report that combined 5-cytosine methylation (5mC) and pseudouridylation (Ψ) of near-cognate non-AUG start codons convert GUG and UUG initiation strongly favored over CUG initiation in eukaryotic translation under a certain context. This prokaryotic-like preference is attributed to enhanced NUG initiation by Ψ in the second base and reduced CUG initiation by 5mC in the first base.
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- The study explored the combined use of CA3, a YAP inhibitor, and trametinib, a MEK inhibitor, to combat resistance seen in neuroblastoma treatment.
- In vitro, CA3 showed promise by reducing cell growth and inducing cell death, while its combination with trametinib exhibited significant synergistic effects in killing cancer cells.
- Although the combination treatment improved survival in xenograft mice, tumors began to regrow after seven weeks, indicating the need for further research to enhance treatment effectiveness and understand the mechanism driving this resistance.
Specific interaction between the start codon, 5'-AUG-3', and the anticodon, 5'-CAU-3', ensures accurate initiation of translation. Recent studies show that several near-cognate start codons (e.g.
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- Researchers studied trametinib, an MEK inhibitor, for its anti-tumor effects on neuroblastoma, finding it effective short-term but not preventing relapse after long-term use for bulky tumors.
- They developed a local minimal residual disease (L-MRD) model in nude mice to test trametinib's effectiveness post-surgery, finding that mice receiving trametinib showed significantly less tumor relapse.
- The study concluded that trametinib could be a promising maintenance therapy following surgery and chemotherapy for neuroblastoma, despite relapses occurring after stopping the drug.
Article Synopsis
- DNA methylation plays a significant role in regulating gene expression and may also influence the physical properties of DNA molecules.
- This study utilized molecular dynamics simulations to investigate how different methylation patterns affect the structure and behavior of double-stranded DNA.
- Results indicated that methylation alters nucleotide positioning and local flexibility, impacting the overall geometry and stiffness of DNA, which may be important for understanding DNA dynamics in biological contexts.
Article Synopsis
- * Current methods convert 2D Hi-C data into static 3D models, but there's a need to explore the dynamic, 4D nature of genomes.
- * The new method PHi-C simulates these 4D genome features from 2D Hi-C data, allowing researchers to analyze how genomic locations and chromosomes interact over time, and it's available for public use.
Article Synopsis
- The study investigates the role of MAPK pathway mutations in relapsed neuroblastomas, particularly focusing on the significance of phosphorylated ERK (pERK) as a potential prognostic indicator.
- Samples from neuroblastoma patients were examined for pERK levels both before and after chemotherapy, with researchers looking for correlations between pERK positivity and patient outcomes.
- Results indicate that post-chemotherapeutic nuclear pERK positivity may be linked to poorer prognosis, suggesting that targeting this pathway with MEK inhibitors could be a viable treatment approach.
Histone Tail Dynamics in Partially Disassembled Nucleosomes During Chromatin Remodeling.
Front Mol Biosci
November 2019
Nucleosomes are structural units of the chromosome consisting of DNA wrapped around histone proteins, and play important roles in compaction and regulation of the chromatin structure. While the structure and dynamics of canonical nucleosomes have been studied extensively, those of nucleosomes in intermediate states, that occur when their structure or positioning is modulated, have been less understood. In particular, the dynamic features of partially disassembled nucleosomes have not been discussed in previous studies.
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- Simple protein elastic networks often provide reasonable predictions of protein dynamics without detailed amino acid data, making them widely used.
- Newer models incorporating sequence-specific and distance-dependent interactions show improved agreement with experimental data but still struggle with predicting fluctuations in flexible regions.
- Overall, both traditional and newer network models tend to overestimate fluctuations in weakly connected residues, and incorporating chemical information has minimal impact on improving prediction accuracy.
Article Synopsis
- The study explored the impact of removing local tumors on the spread of neuroblastoma metastases in mice, specifically looking at how it affects the development of microscopic lymph node metastases (mLNM).
- Researchers found that when local tumors reached a certain size threshold, their removal actually led to a higher rate of metastasis compared to not removing them, with a significant difference in metastatic ratios and lymph node volumes between the surgical and observation groups.
- The results suggest that local tumor resection in cases of high-risk neuroblastoma may potentially accelerate the growth of existing metastases, indicating the need for careful timing of such procedures.
Article Synopsis
- The activity of biological cells relies on complex chemical reactions, typically represented by reaction-diffusion systems, but is influenced by the crowded presence of macromolecules and molecular machines.
- The proposed model simulates these interactions using particles whose shapes change based on internal states and incorporates motion interference through excluded volume repulsion, leading to unique patterns and synchronization behaviors.
- This straightforward and adaptable model aims to explore the interaction between the physical dynamics of molecular machinery and chemical reactions in cells, with potential applications to larger biological systems like cell crowds.
Article Synopsis
- - Elastic networks are simplified models of proteins made up of point particles linked by springs, which help researchers analyze protein dynamics more easily.
- - These models are less computationally intensive than all-atom models, making them ideal for comparing different protein structures and conducting dynamic simulations.
- - The review highlights examples of studies using elastic network models, exploring nonlinear behaviors and their relevance to large macromolecular assemblies.
Recently, the design of mechanical networks with protein-inspired responses has become increasingly popular. Here, we review contributions which were motivated by studies of protein dynamics employing coarse-grained elastic network models. First, the concept of evolutionary optimization that we developed to design network structures which execute prescribed tasks is explained.
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- G protein-coupled receptors (GPCRs) are important targets in drug development, but it's challenging to measure their activity directly at the cell surface.
- Researchers have developed a single-molecule imaging method to assess GPCR activity by observing the movement of metabotropic glutamate receptor 3 (mGluR3) under different ligand conditions using total internal reflection fluorescence microscopy (TIRFM).
- The study found that changes in the receptor's diffusion rate corresponded to its activation or inactivation, and this approach is applicable to various GPCRs, providing a reliable way to gauge the effects of drugs across different receptor types.
Article Synopsis
- The mammalian genome is organized in a 3D structure, divided into large chromatin domains that play essential roles in regulating genome functions.
- Researchers have developed a mathematical model to analyze nucleosome movement within these chromatin domains, revealing that smaller and more compact domains restrict nucleosome mobility.
- This study highlights the relationship between chromatin dynamics and organization, suggesting that understanding this organization can enhance our knowledge of how genomes function in the active, noisy environment of living cells.
Coarse-grained models of DNA have made important contributions to the determination of the physical properties of genomic DNA, working as a molecular machine for gene regulation. In this study, to analyze the global dynamics of long DNA sequences with consideration of sequence-dependent geometry, we propose elastic network models of DNA where each particle represents nucleotides (1-particle-per-k-nucleotides, 1PkN). The models were adjusted according to profiles of the anisotropic fluctuations obtained from our previous 1-particle-per-1-nucleotide (1P1N) model, which was proven to reproduce such profiles of all-atom models.
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- TALEN (Transcription Activator-Like Effector Nuclease) is a popular tool for genome editing, utilizing a series of TAL-repeats that recognize specific DNA bases through unique mutations.
- A modified version of TALEN, called VT-TALE, has mutations at non-RVD positions, which enhances its effectiveness in genome editing by improving target recognition and specificity compared to the standard CT-TALE.
- Research shows that VT-TALE exhibits greater superhelical motion, facilitated by altered hydrogen bonding between TAL-repeats, leading to better engagement with target DNA sequences.
Article Synopsis
- The study examines how chromatin domains (CDs) in mammalian genomes, specifically topologically associating domains, are structured and function during nucleosome movement.
- Through a polymer model, researchers demonstrate that the movement of nucleosomes within these domains is subdiffusive, affected by the compactness of CDs in different nuclear regions.
- Findings reveal that CDs are approximately 100-500 nm in size and that nucleosome movement has a relaxation time of a few seconds, enhancing the understanding of genome architecture in live cells.
Article Synopsis
- Cell activities rely on chemical reactions, particularly those facilitated by enzymes, which are modeled as catalytic reaction networks.
- Traditional modeling with ordinary differential equations may not accurately capture behavior when there are few molecules, highlighting the need for new approaches that consider small-number phenomena.
- This study develops an analytical framework for the chemical master equation to analyze catalytic reaction networks, applying the probability generating function method to derive steady-state solutions and exploring implications for real biochemical pathways.
Integrin LFA-1 regulates cell adhesion via transient clutch formation.
Biochem Biophys Res Commun
August 2015
Integrin LFA-1 regulates immune cell adhesion and trafficking by binding to ICAM-1 upon chemokine stimulation. Integrin-mediated clutch formation between extracellular ICAM-1 and the intracellular actin cytoskeleton is important for cell adhesion. We applied single-molecule tracking analysis to LFA-1 and ICAM-1 in living cells to examine the ligand-binding kinetics and mobility of the molecular clutch under chemokine-induced physiological adhesion and Mn(2+)-induced tight adhesion.
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- Transformations between G-actin (monomeric) and F-actin (polymeric) play a key role in important cellular processes like migration and division.
- The researchers used advanced microscopy techniques to observe how individual actin proteins change their shape and state.
- Their findings reveal that these shape changes occur over hundreds of seconds and vary based on the environment, indicating that actin can adapt structurally to promote polymerization.
Article Synopsis
- - Researchers used an elastic-network model to study how G-actin (a type of protein) changes shape when subjected to mechanical forces, finding that it acts like a strain sensor with defined movements in response to stress.
- - The study identified specific residues in the nucleotide-binding pocket (NBP) of G-actin that, when altered, can lead to significant changes in the protein's shape, including flattening and closing of its active sites.
- - The introduction of breakable links in the model revealed that G-actin can exist in a closed, stable state influenced by ATP, suggesting that ATP enhances G-actin's ability to polymerize quickly.