Biology subjects

Mori, Y.

Publications and source records attributed to Mori, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

A conservative moving-boundary multiphysics framework reveals nonlinear coupling between osmotic flow and actin-driven cell migration

Cell migration couples membrane transport, intracellular fluid motion, and actin remodeling on a boundary that deforms with the cell. Quantitative interpretation of this coupling requires accurate one-sided membrane solute transport and conservative transfer between the G-actin and F-actin pools, because these fields determine the osmotic pressure and polymerization flux that enter the force balance. We develop an implicit immersed-boundary Stokes--Brinkman solver coupled to a sharp interface Cartesian grid advection--diffusion solver that enforces Robin conditions on the evolving membrane and advances F-actin/G-actin exchange through paired interface fluxes on the same accepted geometry. The framework resolves membrane mechanics, osmotic water permeation, solute transport, actin turnover, substrate drag, and intracellular advection in one calculation. Long-duration tests show excellent conservation of total actin and total solute under sustained interface motion and transport. The actin calculations recover biphasic dependencies on both depolymerization and substrate coupling, while pump-induced migration generates a rearward cell-relative cytosolic flow. In the fully coupled system, this flow redistributes G-actin more strongly than F-actin, reorganizes membrane polymerization and F-actin stress, and changes cell migration. Matched controls show that the coupled actin--osmotic system travels farther than the baseline-corrected sum of the isolated actin- and pump-driven responses. The calculations identify cytosolic convection as a physical route through which polarized membrane transport reorganizes the force-generating actin system and produces a nonlinear migration response.

biophysics↗

bioRxiv2026

Lasp family proteins generated by teleost-specific genome duplication

Two rounds of whole-genome duplication (2R-WGD) in the vertebrate lineage are thought to have driven gene diversification. Mammals have four genes encoding five nebulin superfamily proteins (LASP1, LASP2/NEBL, NEB, and NRAP) hypothesised to have arisen from invertebrate LASP via WGD. Here, we examined the evolutionary fate of the nebulin superfamily after an additional WGD, teleost-specific genome duplication (TGD). Genome and transcriptome analysis of zebrafish (Danio rerio) and medaka (Oryzias latipes), of which the complete genomes were recently determined, showed only lasp family genes retained duplicate copies. Zebrafish retained two LASP2/NEBL-derived ohnologs; one (LASP2L) had been misidentified as a nebulette gene in the Zebrafish Information Network (ZFIN) despite lacking nebulette-specific exons. Another (LASP2/NEBL) is newly identified in this study because it lies in a newly determined region of the latest genome assembly. Contrastingly, medaka retained two LASP1 ohnologs and one LASP2/NEBL. The duplicated lasp family proteins showed overlapping and specific tissue expression patterns. We confirmed all three zebrafish lasp proteins bound actin and co-localized with actin-rich structures when ectopically expressed in cultured fibroblasts. This supports that TGD-derived lasp duplicates underwent lineage-specific retention and expression divergence in teleosts whilst conserving core actin-binding properties.

evolutionary biology↗

bioRxiv2026

Autonomic and neurotrophic signaling in alcohol-associated liver disease

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, yet its pathogenesis remains incompletely understood. While neural regulation is critical for hepatic homeostasis, how autonomic and neurotrophic signaling is regulated in the liver during ALD progression remains largely unexplored. Here, we performed an integrative analysis of bulk and single-cell transcriptomic datasets of human livers across the spectrum of ALD. We identified stage-dependent remodeling and coordinated expression patterns of autonomic and neurotrophic genes. Autonomic signaling exhibited a consistent decline, with reduced expression of sympathetic (DBH, TH) and the parasympathetic (ChAT) markers. In contrast, pan-neuronal and neuroplasticity-associated genes (UCHL1, TUBB3, STMN2) were upregulated, indicating active neural remodeling. In parallel, factors such as MANF, GDNF, and NRG2, with the receptor NTRK1, were upregulated and positively correlated with clinical indicators of disease severity, inflammation and fibrosis. In contrast, trophic factors including NTF3 and CDNF, and receptors such as GFRA1 and GFRA3, were downregulated and inversely associated with these parameters. Single-cell analyses revealed that neurotrophic factors are predominantly expressed by hepatic stellate cells, supporting their role as resident neuroglia-like cells in the liver. In another independent cohort, we observed a coordinated downregulation of NTF3 and sympathetic nerve markers in alcohol-associated hepatitis (AH), suggesting impaired NTF3-mediated neurotrophic support may contribute to sympathetic dysfunction in AH. Collectively, these findings uncover previously unrecognized neuro-regulatory dimensions in ALD and suggest that dysregulated autonomic and neurotrophic signaling may contribute to disease progression. Conflict of interestThe authors have declared that no conflict of interest exists.

bioinformatics↗

bioRxiv2026

Cycling persister clones with elevated NR2F1-mediated cholesterol biosynthesis cause chemotherapy resistance

While a subpopulation termed cycling persisters (CPs) that is characterized by sustained proliferation, even under chemotherapy drug exposure, contributes more directly to tumor relapse, the molecular basis for the emergence of CPs has been unclear. Here, we used the human tongue cancer organoid (TCO) library to continuously track the in vitro fate of individual cancer cell clones during and after chemotherapy exposure using time-lapse imaging. Among the heterogeneous clones, we identified CPs that formed larger clusters than the others, which barely grew and remained small (non-CPs). Using differences in cell cluster size as an indicator, thousands of CP and non-CP clones were directly sampled from 3D matrix organoid cultures and were analyzed. Notably, tumor-intrinsic interferon (IFN) signaling and hypoxic pathways were inactivated, whereas the NR2F1-mediated cholesterol biosynthesis pathway was distinctly activated in CPs compared to non-CPs. Indeed, inhibiting cholesterol biosynthesis with simvastatin significantly suppressed the appearance of CP clones, showing that elevated cholesterol biosynthesis is essential for the emergence of CPs. These findings suggest that clonal-level variations in the intensity of these signaling pathways determine the fate of individual tumor cells exposed to chemotherapeutic agents, which may provide insights into cancer relapse mechanisms and identify potential molecular targets of CPs.

cancer biology↗

bioRxiv2026

Spatial navigation through evolution: a single-cell atlas of the mammalian entorhinal cortex

Spatial navigation is a fundamental mammalian ability, supported by the entorhinal cortex (EC), a structurally conserved yet functionally diverse region across mammalian species. However, how molecular signaling underlies both shared and species-specific navigational strategies remains unclear. Here, we present a cross-species single-cell atlas of the EC from human, Hamadryas baboon, mouse, and Egyptian fruit bat - species spanning distinct evolutionary lineages and navigational demands, including true 3D navigation in bats. Using this resource, we identify conserved principal neuron populations as well as species-specific innovations, including mixed-layer or functional identities and fruit bat-specific subtypes. GABAergic interneurons neurons show strong conservation of somatostatin (SST) and parvalbumin (PV) families, while VIP GABAergic neurons exhibit pronounced species-specific divergence, with an expanded repertoire in primates. Integration with whole-brain diffusion tensor imaging reveals conserved and species-specific connectivity between the EC, hippocampus, and sensory cortices. Major species-specific cellular innovations were further validated using orthogonal histological approaches, confirming their anatomical and laminar organization. Overall, this atlas provides a comparative framework available for the research community to dissect the molecular, cellular, and circuit principles underlying conserved and specialized spatial navigation across mammals.

neuroscience↗

bioRxiv2025

Tegmental atrophy in isolated REM sleep behaviour disorder: Ex vivo-informed in vivo imaging

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is an early-stage synucleinopathy characterized by brainstem pathology. In rodents, the pontine tegmentum contains an REM sleep centre, the sublaterodorsal nucleus (SLD), which expresses corticotropin-releasing hormone binding protein (CRHBP). While the involvement of brainstem pathophysiology is thus implicated in iRBD, its solid evidence remains scarce in humans due to the difficulty in identifying small brainstem nuclei with conventional MRI technology alone. Here, we aimed to detect tegmental atrophy in iRBD with voxel-based morphometry (VBM) analysis combined with a novel human brainstem atlas. Structural MRIs from 98 patients with iRBD and 114 controls were analysed to investigate grey matter volume (GMV) using VBM. Our unique approach involved detailed assessments of the VBM results, guided by a high-resolution MRI-based atlas of the human brainstem. This brainstem atlas was founded on ex vivo MRI of 10 postmortem human specimens. We validated it with CRHBP immunostaining, which aided in identifying putative REM sleep-regulating nuclei in humans. We applied this brainstem atlas to identify atrophy in specific brainstem regions in iRBD and correlate their volumes with clinical measures, including autonomic functions. VBM revealed a focal cluster of grey matter atrophy in the dorsal pontine tegmentum of iRBD patients, including the laterodorsal tegmental nucleus, ventral part (LDTgV) and the pedunculopontine tegmental nucleus (PTg). Our atlas-based analysis confirmed the LDTgV as the site of most conspicuous atrophy, revealing a significant volume reduction in iRBD patients compared to controls with a moderate effect size (Cohens d = 0.46, Bonferroni-corrected p = 0.019). Furthermore, greater atrophy in the LDTgV and the PTg was associated with more severe autonomic dysfunction as measured by Scales for Outcomes in Parkinsons Disease-Autonomic dysfunction (SCOPA-AUT) scores (partial r = -0.237, p = 0.019 and partial r = -0.236, p = 0.019, respectively). Histological analysis confirmed that the LDTgV is selectively enriched with CRHBP-positive neurons, a putative marker for REM sleep-on neurons. We provided novel evidence for the involvement of LDTgV, the putative human homolog of the murine SLD, in iRBD. The present findings advance our understanding of the neuroanatomical basis of iRBD and will contribute to the development of early biomarkers for -synucleinopathies.

neuroscience↗

bioRxiv2025

A self-limiting mechanotransduction feedback loop ensures robust organ formation

Organ morphogenesis uses mechanotransduction feedback loops to convert forces into gene expression changes that regulate cell mechanics. How these loops integrate with developmental programs to ensure robust outcomes remains unclear. We show Yap mechanotransduction establishes a self-limiting positive feedback loop for semicircular canal formation in zebrafish. Canal development proceeds through bud initiation, extension, and fusion within the otic epithelium. Local swelling of hyaluronan-rich extracellular matrix (ECM) in the bud activates Yap in a spatial pattern. Yap induces its target ccn1l1, promoting further ECM expansion to sustain bud extension. This feedback loop confers developmental robustness: graded knockdown of ccn1l1 reduces extension rate, yet canal formation persists and fails only with strong disruption. Critically, the loop contains its own termination mechanism. During bud fusion, PKA-CREB signaling, activated by an adhesion GPCR, gpr126, suppresses ccn1l1, ending the loop. These findings reveal how mechanotransduction loops with built-in termination provide developmental control by integrating mechanical forces, transcriptional responses, and morphogenetic outcomes.

developmental biology↗

bioRxiv2025

MR-AIV reveals in-vivo brain-wide fluid flow with physics-informed AI

The circulation of cerebrospinal and interstitial fluid plays a vital role in clearing metabolic waste from the brain, and its disruption has been linked to neurological disorders. However, directly measuring brain-wide fluid transport--especially in the deep brain--has remained elusive. Here, we introduce magnetic resonance artificial intelligence velocimetry (MR-AIV), a framework featuring a specialized physics-informed architecture and optimization method that reconstructs three-dimensional fluid velocity fields from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MR-AIV unveils brain-wide velocity maps while providing estimates of tissue permeability and pressure fields--quantities inaccessible to other methods. Applied to the brain, MR-AIV reveals a functional landscape of interstitial and perivascular flow, quantitatively distinguishing slow diffusion-driven transport ([~] 0.1 {micro}m/s) from rapid advective flow ([~] 3 {micro}m/s). This approach enables new investigations into brain clearance mechanisms and fluid dynamics in health and disease, with broad potential applications to other porous media systems, from geophysics to tissue mechanics.

neuroscience↗

bioRxiv2025

Speak or shout? Nonverbal vocalizations ensure rapid detection of emotions in vocal communication

Human vocal expressions of emotion can be expressed nonverbally, through vocalizations such as shouts or laughter, or speakers can embed emotional meanings in language by modifying their tone of voice ("prosody"). Is there evidence that nonverbal expressions promote "better" (i.e., more accurate, faster) recognition of emotions than speech, and what is the impact of language experience? Our study investigated these questions using a cross-cultural gating paradigm, in which Chinese and Arab listeners (n=25/group) judged the emotion communicated by acoustic events that varied in duration (200 milliseconds to the full expression) and form (vocalizations or prosody expressed in listeners native, second or foreign language). Accuracy was higher for vocalizations overall, but listeners were markedly more efficient to form stable categorical representations of the speakers emotion from vocalizations (M = 417ms) than native prosody (M = 765ms). Language experience enhanced recognition of emotional prosody expressed by native/ingroup speakers for some listeners (Chinese) but not all (Arab), emphasizing the dynamic interplay of socio-cultural factors and stimulus quality on prosody recognition which occurs over a more sustained time window. Our data show that vocalizations are functionally suited to build robust, rapid impressions of a speakers emotion state unconstrained by the listeners linguistic cultural background.

animal behavior and cognition↗

bioRxiv2024

Glymphatic clearance is enhanced during sleep

We here revisited the concept that glymphatic clearance is enhanced by sleep and anesthesia. Utilizing dynamic magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and fluorescent fiber photometry, we report brain glymphatic clearance is enhanced by both sleep and anesthesia, and sharply suppressed by wakefulness. Another key finding was that less tracer enters the brains of awake animals and that brain clearance across different brain states can only be compared after adjusting for the injected tracer dose.

neuroscience↗

bioRxiv2024

Stabilization Mechanism of Initiator Transfer RNA in the Small Ribosomal Subunit from Coarse-Grained Molecular Simulations

Proteins play a variety of roles in biological phenomena in cells. Proteins are synthesized by a ribosome, which is a large molecular complex composed of proteins and nucleic acids. Among many molecules involved in the process of protein synthesis, transfer RNA (tRNA) is one of the essential molecules. In this study, coarse-grained molecular dynamics simulations were performed to understand how the tRNA molecule is stabilized in the ribosome, and the free energy along the dissociation path of the tRNA was calculated. We found that some ribosomal proteins, which are components of the ribosome, are involved in the stabilization of the tRNA. The positively charged amino acid residues in the C-terminal region of the ribosomal proteins are particularly important for the stabilization. These findings contribute to our understanding of the molecular evolution of protein synthesis in terms of the ribosome, which is a universal component of life. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/603193v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@180f160org.highwire.dtl.DTLVardef@671705org.highwire.dtl.DTLVardef@187fd6org.highwire.dtl.DTLVardef@70c5ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2024

Versican controlled by Lmx1b regulates hyaluronate density and hydration for semicircular canal morphogenesis

During inner ear semicircular canal morphogenesis in zebrafish, patterned canal-genesis zones express genes for extracellular matrix component synthesis. These include hyaluronan and the hyaluronan-binding chondroitin sulfate proteoglycan Versican, which are abundant in the matrices of many developing organs. Charged hyaluronate polymers play a key role in canal morphogenesis through osmotic swelling. However, the developmental factor(s) that control the synthesis of the matrix components and regulation of hyaluronate density and swelling are unknown. Here, we identify the transcription factor, Lmx1b, as a positive transcriptional regulator of hyaluronan, Versican, and chondroitin synthesis genes crucial for canal morphogenesis. We show that Versican regulates hyaluronan density through its protein core, whereas the charged chondroitin side chains contribute to the osmotic swelling of hyaluronate. Versican-tuned properties of hyaluronate matrices may be a broadly used mechanism in morphogenesis with important implications for understanding diseases where these matrices are impaired, and for hydrogel engineering for tissue regeneration. Summary StatementHere, we reveal the function of the hyaluronan-binding proteoglycan, Versican, and its chondroitin sulfate side chains in tuning the density and hydration of the hyaluronate-rich ECM to generate force, under the control of the transcription factor Lmx1b for successful inner ear semicircular canal morphogenesis in zebrafish.

developmental biology↗

bioRxiv2024

An electrodiffusive network model with multicompartmental neurons and synaptic connections

Most computational models of neurons assume constant ion concentrations, disregarding the effects of changing ion concentrations on neuronal activity. Among the models that do incorporate ion concentration dynamics, shortcuts are often made that sacrifice biophysical consistency, such as neglecting the effects of ionic diffusion on electrical potentials or the effects of electric drift on ion concentrations. A subset of models with ion concentration dynamics, often referred to as electrodiffusive models, account for ion concentration dynamics in a way that ensures a biophysical consistent relationship between ion concentrations, electric charge, and electrical potentials. These models include compartmental single-cell models, geometrically explicit models, and domain-type models, but none that model neuronal network dynamics. To address this gap, we present an electrodiffusive network model with multicompartmental neurons and synaptic connections, which we believe is the first compartmentalized network model to account for intra- and extracellular ion concentration dynamics in a biophysically consistent way. The model comprises an arbitrary number of "units," each divided into three domains representing a neuron, glia, and extracellular space. Each domain is further subdivided into a somatic and dendritic layer. Unlike conventional models which focus primarily on neuronal spiking patterns, our model predicts intra- and extracellular ion concentrations (Na+, K+, Cl-, and Ca2+), electrical potentials, and volume fractions. A unique feature of the model is that it captures ephaptic effects, both electric and ionic. In this paper, we show how this leads to interesting behavior in the network. First, we demonstrate how changing ion concentrations can affect the synaptic strengths. Then, we show how ionic ephaptic coupling can lead to spontaneous firing in neurons that do not receive any synaptic or external input. Lastly, we explore the effects of having glia in the network and demonstrate how a strongly coupled glial syncytium can prevent neuronal depolarization blocks. Author summaryNeurons communicate using electrical signals called action potentials. To create these signals, sodium ions must flow into the cells and potassium ions must flow out. This transmembrane flow requires a concentration difference across the neuronal membrane, which the brain works continuously to maintain. When scientists build mathematical models of neurons, they often apply the simplifying assumption that these ion concentration differences remain constant over time. This assumption works well for many scenarios, but not all. For instance, during events like stroke or epilepsy, the ion concentrations can change dramatically, affecting how neurons behave. Moreover, recent literature suggests that changing ion concentrations also play an important role in normal brain function. To study these scenarios, we need models that can dynamically track changes in ion concentrations. The neuroscience community currently lacks a computational model describing the effects of ion concentration dynamics on neuronal networks, while maintaining a biophysical consistent relationship between ion concentrations and electrical potentials. To address the need for such a model, we have developed a neuronal network model that predicts changes in both intra- and extracellular ion concentrations, electrical potentials, and volumes in a biophysically consistent way.

neuroscience↗

bioRxiv2024

A Mathematical Framework for Comparison of Intermittent and Continuous Adaptive Chemotherapy Dosing in Cancer

Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intra-tumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed dose or continuously at a variable dose based on tumor size, may lengthen progression free survival over traditional dosing [1]. Indeed, in mathematical models using modified Lotka Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed [2]. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms. Significance StatementIntra-tumoral cell-cell competition between drug resistant and drug sensitive cancer cells is hypothesized to drive resistance development after chemotherapy administration in certain cancers. Optimization of chemotherapy delivery through dose or schedule adaptation based on tumor parameters (adaptive therapy) has been hypothesized to utilize chemotherapy sensitive cells to compete with chemotherapy resistant cells and delay tumor outgrowth. Here, we develop an analytical framework to compare two alternative adaptive therapy approaches: dose modulation (continuous) and schedule modulation (intermittent). Through direct analytical comparison, we demonstrate that continuous adaptive therapy is superior to intermittent adaptive therapy across physiologically relevant metrics. Furthermore, in parameters spaces where resistant population extinction is feasible, traditional fixed-dose therapy at a low dose may carry additional benefits over adaptive therapy.

systems biology↗

bioRxiv2023

Structural characterization of SLYM - a 4th cranial meningeal membrane

Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1-3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.

neuroscience↗

bioRxiv2023

ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease

AMP-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular adenosine monophosphate (AMP) levels result in AMPK activation through the binding of AMP to the {gamma}-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. In this study, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPK{gamma}1 at Ser260/Thr262 promotes AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1-/- mice despite an increased AMP/ATP ratio. We also demonstrated that MK8722, an allosteric AMPK activator, activates AMPK in the kidneys of a CKD mouse model via a pathway that is independent of AMP sensing. MK8722 treatment significantly attenuates the deterioration of renal function in CKD and is a potential therapeutic option in CKD therapeutics.

molecular biology↗

bioRxiv2023

Anesthetic-Binding Induced Motion of GABA A Receptors Revealed by Coarse-Grained Molecular Dynamics Simulations

General anesthetics are indispensable in modern medicine because they induce a reversible loss of consciousness and sensation in humans. On the other hand, their molecular mechanisms of action have not yet been elucidated. Several studies have identified the main targets of some general anesthetics. The structures of {gamma}-aminobutyric acid A (GABAA) receptors with the intravenous anesthetics such as propofol and etomidate have recently been determined. Although these anesthetic-binding structures provide essential insights into the mechanism of action of anesthetics, the detailed molecular mechanism of how the anesthetic binding affects the Cl- permeability of GABAA receptors remains to be elucidated. In this study, we performed coarse-grained molecular dynamics simulations for GABAA receptors and analyzed the resulting simulation trajectories to investigate the effects of anesthetic binding on the motion of GABAA receptors. The results showed large structural fluctuations in GABAA receptors, correlations of motion between the amino-acid residues, large amplitude motion, and autocorrelated slow motion, which were obtained by advanced statistical analyses. In addition, comparison of the resulting trajectories in the presence or absence of the anesthetic molecules revealed a characteristic pore motion related to the gate-opening motion of GABAA receptors.

biophysics↗

bioRxiv2022

End-to-end protein-ligand complex structure generation with diffusion-based generative models

Three-dimensional structures of protein-ligand complexes provide valuable insights into their interactions and are crucial for molecular biological studies and drug design. However, their high-dimensional and multimodal nature hinders end-to-end modeling, and earlier approaches depend inherently on existing protein structures. To overcome these limitations and expand the range of complexes that can be accurately modeled, it is necessary to develop efficient end-to-end methods. We introduce an equivariant diffusion-based generative model that learns the joint distribution of ligand and protein conformations conditioned on the molecular graph of a ligand and the sequence representation of a protein extracted from a pre-trained protein language model. Benchmark results show that this protein structure-free model is capable of generating diverse structures of protein-ligand complexes, including those with correct binding poses. Further analyses indicate that the proposed end-to-end approach is particularly effective when the ligand-bound protein structure is not available. The present results demonstrate the effectiveness and generative capability of our end-to-end complex structure modeling framework with diffusion-based generative models. We suppose that this framework will lead to better modeling of protein-ligand complexes, and we expect further improvements and wide applications.

bioinformatics↗