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Jung, J.

Publications and source records attributed to Jung, J..

At least 91 records · Page 5Linked to original sources

Auditory selective attention during a working memory task with melodies: a MEG study

Working memory and attention are jointly needed in most everyday life tasks and activities. They have however mostly been studied separately. Here we investigate how auditory working memory and selective attention interact using a recently introduced paradigm (MEMAT) that combines a classic working memory paradigm, the delayed-matching-to-sample task, and selective attention, with distractors presented during the encoding phase. All stimuli are four-tone melodies. Twenty-two participants performed the MEMAT task during MEG recordings. We manipulate the difficulty of the memory task and of attentional filtering. When memory task difficulty increases, the amplitude of the CNV in anticipation of the melody to encode increases and the decrease in alpha power during encoding and maintenance in a left fronto-temporal network is reduced. When attentional filtering difficulty increases, the amplitude of the sustained evoked response during encoding increases, whereas the differential processing of relevant and irrelevant sounds in auditory areas is less pronounced, and frontal theta power during encoding and maintenance is higher. In the left auditory cortex, we could directly observe the result of the interaction between auditory memory and attention: the facilitation of relevant sound processing in the easy filtering condition was reduced when the memory task difficulty increased. This pattern mirrors the observed behavioral effects. Overall brain dynamics highlight reciprocal influences of working memory and selective attention processes, in keeping with shared cognitive resources between them.

neuroscience↗

GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamicload balancing for heterogeneous biomolecular systems

Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution. The new schemes are applied to intrinsically disordered protein (IDP) droplet fusions. The droplet shape changes correlate with mixing IDP chains from two droplets. We also simulate formations of large IDP droplets, whose sizes are almost equivalent to those observed in microscopy. The methods have been implemented in CGDYN of the GENESIS software, which provides a new tool for investigating mesoscopic biological phenomena using the residue-level CG models.

biophysics↗

KoNA: Korean Nucleotide Archive as a New Data Repository for Nucleotide Sequence Data

During the last decade, generation and accumulation of petabase-scale high-throughput sequencing data have resulted in ethical and technical challenges, including access to human data, and transfer, storage, and sharing of enormous amount of data. To promote data-driven research in biology, the Korean government announced that all the biological data generated from government-funded research projects should be deposited in the Korea BioData Station (K-BDS), which consists of multiple databases for individual data types. We introduce the Korean Nucleotide Archive (KoNA), a repository for nucleotide sequence data. As of July 2022, the Korean Read Archive in KoNA has collected over 477 TB of raw next generation sequencing data from several national genome projects. To ensure data quality and prepare for international alignment, a standard operating procedure (SOP) was adopted, which is similar to the International Nucleotide Sequence Database Collaboration. The SOP includes quality control processes for submitted data and metadata using an automated pipeline followed by manual examination. To ensure fast and stable data transfer, a high-speed transmission system called GBox is used in KoNA. Furthermore, the data uploaded to or downloaded from KoNA through GBox can be readily processed in a cloud-computing service for genomic data analysis called Bio-Express. This seamless coupling of KoNA, GBox, and Bio-Express enhances data experience including submission, access, and analysis of raw nucleotide sequences. KoNA not only satisfies the unmet needs for a national sequence repository in Korea, but also provides datasets to researchers globally and contribute to advances in genomics. KoNA is available at https://www.kobic.re.kr/kona/.

genomics↗

A side-by-side comparison of peptide-delivered antisense antibiotics employing different nucleotide mimics

Antisense oligomer (ASO)-based antibiotics that target mRNAs of essential bacterial genes have great potential for counteracting antimicrobial resistance and for precision microbiome editing. To date, the development of such antisense antibiotics has primarily focused on using phosphorodiamidate morpholino (PMO) and peptide nucleic acid (PNA) backbones, largely ignoring the growing number of chemical modalities that have spurred the success of ASO-based human therapy. Here, we directly compare the activities of seven chemically distinct 10mer ASOs, all designed to target the essential gene acpP upon delivery with a KFF-peptide carrier into Salmonella. Our systematic analysis of PNA, PMO, phosphorothioate-modified DNA (PTO), 2-methylated RNA (RNA-OMe), 2-methoxyethylated RNA (RNA-MOE), 2-fluorinated RNA (RNA-F) and 2-4-locked RNA (LNA) is based on a variety of in vitro and in vivo methods to evaluate ASO uptake, target pairing and inhibition of bacterial growth. Our data show that only PNA and PMO are efficiently delivered by the KFF peptide into Salmonella to inhibit bacterial growth. Nevertheless, the strong target binding affinity and in vitro translational repression activity of LNA and RNA-MOE make them promising modalities for antisense antibiotics that will require the identification of an effective carrier.

microbiology↗

Revealing the Organ-Specific Expression of SPTBN1 using Single-Cell RNA Sequencing Analysis

Despite the recent technological advances in single-cell RNA sequencing, it is still unknown how three marker genes (SPTBN1, EPDR1, and PKDCC), which are associated with bone fractures and highly expressed in the muscle tissue, are contributing to the development of other tissues and organs at the cellular level. This study aims to analyze three marker genes at the single-cell level using 15 organ tissue types of adult human cell atlas (AHCA). The single-cell RNA sequencing analysis used three marker genes and a publicly available AHCA data set. AHCA data set contains more than 84,000 cells from 15 organ tissue types. Quality control filtering, dimensionality reduction, clustering for cells, and data visualization were performed using the Seurat package. A total of 15 organ types are included in the downloaded data sets: Bladder, Blood, Common Bile Duct, Esophagus, Heart, Liver, Lymph Node, Marrow, Muscle, Rectum, Skin, Small Intestine, Spleen, Stomach, and Trachea. In total, 84,363 cells and 228,508 genes were included in the integrated analysis. A marker gene of SPTBN1 is highly expressed across all 15 organ types, particularly in the Fibroblasts, Smooth muscle cells, and Tissue stem cells of the Bladder, Esophagus, Heart, Muscle, Rectum, Skin, and Trachea. In contrast, EPDR1 is highly expressed in the Muscle, Heart, and Trachea, and PKDCC is only expressed in Heart. In conclusion, SPTBN1 is an essential protein gene in physiological development and plays a critical role in the high expression of fibroblasts in multiple organ types. Targeting SPTBN1 may prove beneficial for fracture healing and drug discovery. Author SummaryThree marker genes (SPTBN1, EPDR1, and PKDCC) are playing a critical role in the shared genetic mechanisms between bone and muscle. However, how these marker genes contribute to developing other tissues and organs at the cellular level is unknown. Here, we build on prior work to study an unappreciated degree of heterogeneity of three marker genes in 15 adult human organs by using single-cell RNA sequencing technology. Our analysis included 15 organ types: Bladder, Blood, Common Bile Duct, Esophagus, Heart, Liver, Lymph Node, Marrow, Muscle, Rectum, Skin, Small Intestine, Spleen, Stomach, and Trachea. In total, 84,363 cells from 15 different organ types were included. In all 15 organ types, SPTBN1 is highly expressed, including fibroblasts, smooth muscle cells, and skin stem cells of the bladder, esophagus, heart, muscles, and rectum. The first-time discovery of the high expression of SPTBN1 in 15 organ types suggests that it may play a critical role in physiological development. Our study concludes that targeting SPTBN1 may benefit fracture healing and drug discovery.

bioinformatics↗

Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia

Microglia play a pivotal role in neurodegenerative disease pathogenesis, but the mechanisms underlying microglia dysfunction and toxicity remain to be fully elucidated. To investigate the effect of neurodegenerative disease-linked genes on the intrinsic properties of microglia, we studied microglia-like cells derived from human induced pluripotent stem cells (iPSCs), termed iMGs, harboring mutations in profilin-1 (PFN1) that are causative for amyotrophic lateral sclerosis (ALS). ALS-PFN1 iMGs exhibited lipid dysmetabolism and deficits in phagocytosis, a critical microglia function. Our cumulative data implicate an effect of ALS-linked PFN1 on the autophagy pathway, including enhanced binding of mutant PFN1 to the autophagy signaling molecule PI3P, as an underlying cause of defective phagocytosis in ALS-PFN1 iMGs. Indeed, phagocytic processing was restored in ALS-PFN1 iMGs with Rapamycin, an inducer of autophagic flux. These outcomes demonstrate the utility of iMGs for neurodegenerative disease research and highlight microglia vesicular degradation pathways as potential therapeutic targets for these disorders.

neuroscience↗

Shared Genetic Architecture between Muscle and Bone: Identification and Functional Implications of EPDR1, PKDCC, and SPTBN1

Recent studies suggest a shared genetic architecture between muscle and bone, yet the underlying molecular mechanisms remain elusive. This study aims to identify the functionally annotated genes with shared genetic architecture between muscle and bone using the most up-to-date genome-wide association study (GWAS) summary statistics from bone mineral density (BMD) and fracture-related genetic variants. We employed an advanced statistical functional mapping method to investigate shared genetic architecture between muscle and bone, focusing on genes highly expressed in muscle tissue. Our analysis identified three genes, EPDR1, PKDCC, and SPTBN1, highly expressed in muscle tissue and previously unlinked to bone metabolism. About 90% and 85% of filtered Single-Nucleotide Polymorphisms were located in the intronic and intergenic regions for the threshold at P [≤] 5 x 10-8 and P [≤] 5 x 10-100, respectively. EPDR1 was highly expressed in multiple tissues, including muscle, adrenal gland, blood vessels, and thyroid. SPTBN1 was highly expressed in all 30 tissue types except blood, while PKDCC was highly expressed in all 30 tissue types except the brain, pancreas, and skin. Our study provides a framework for using GWAS findings to highlight functional evidence of crosstalk between multiple tissues based on shared genetic architecture between muscle and bone. Further research should focus on functional validation, multi-omics data integration, gene-environment interactions, and clinical relevance in musculoskeletal disorders. Author SummaryOsteoporotic fractures in the aging population pose a significant health concern. They are often attributed to decreased bone strength and muscle loss. However, the underlying molecular connections between bone and muscle are not well understood. This lack of knowledge persists despite recent genetic discoveries linking certain genetic variants to bone mineral density and fracture risk. Our study aimed to uncover genes that share genetic architecture between muscle and bone. We utilized state-of-the-art statistical methods and the most recent genetic data related to bone mineral density and fractures. Our focus was on genes that are highly active in muscle tissue. Our investigation identified three new genes - EPDR1, PKDCC, and SPTBN1 - which are highly active in muscle tissue and influence bone health. These discoveries offer fresh insights into the interconnected genetic makeup of bone and muscle. Our work not only uncovers potential targets for therapeutic strategies to enhance bone and muscle strength but also provides a blueprint for identifying shared genetic structures across multiple tissues. This research represents a crucial step forward in our understanding of the interplay between our muscles and bones at a genetic level.

genomics↗

How host-like signals drive gene expression and gene expression drives capsule expansion in Cryptococcus neoformans

Cryptococcus neoformans is an opportunistic fungal pathogen with a polysaccharide capsule that becomes greatly enlarged in the mammalian host and during in vitro growth under host-like conditions. To understand how individual environmental signals affect capsule size and gene expression, we grew cells in all combinations of five signals implicated in capsule size and systematically measured cell and capsule sizes. We also sampled these cultures over time and performed RNA-Seq in quadruplicate, yielding 881 RNA-Seq samples. Analysis of the resulting data sets showed that capsule induction in tissue culture medium, typically used to represent host-like conditions, requires the presence of either CO2 or exogenous cyclic AMP (cAMP). Surprisingly, adding either of these pushes overall gene expression in the opposite direction from tissue culture media alone, even though both are required for capsule development. Another unexpected finding was that rich medium blocks capsule growth completely. Statistical analysis further revealed many genes whose expression is associated with capsule thickness; deletion of one of these significantly reduced capsule size. Beyond illuminating capsule induction, our massive, uniformly collected dataset will be a significant resource for the research community. IMPORTANCECryptococcus neoformans is an opportunistic yeast that kills [~]150,000 people each year. This major impact on human health makes it imperative to understand the basic biology of C. neoformans and the factors that mediate its virulence. One key virulence factor is a polysaccharide capsule that expands greatly during infection. To help define capsule synthesis and fungal biology, we provided cells with many different combinations of host-like signals and sampled the cultures over time for transcriptional analysis. The resulting time resolved data set is by far the largest gene expression resource ever produced for C. neoformans (881 RNA-seq samples), further enriched by accompanying capsule images and measurements. It revealed surprising findings, including that rich medium suppresses capsule size regardless of other signals. This landmark data resource will be enormously valuable to the research community as it continues to define the relationships between environmental signals and cryptococcal gene expression, biology, and virulence.

genomics↗

Dextromethorphan inhibits collagen transport in the endoplasmic reticulum eliciting an anti-fibrotic response in ex-vivo and in vitro models of pulmonary fibrosis

Excessive deposition of fibrillar collagen in the interstitial extracellular matrix (ECM) of human lung tissue causes fibrosis, which can ultimately lead to organ failure. Despite our understanding of the molecular mechanisms underlying the disease, a cure for pulmonary fibrosis has not yet been found. In this study, we screened an FDA-approved drug library containing 712 drugs and found that Dextromethorphan (DXM), a cough expectorant, significantly reduces the amount of excess fibrillar collagen deposited in the ECM in in-vitro cultured primary human lung fibroblasts (NHLF) and ex-vivo cultured human precision-cut lung slice (hPCLS) models of lung fibrosis. Reduced extracellular fibrillar collagen levels in the ECM upon DXM treatment are due to a reversible trafficking inhibition of collagen type I (COL1) in the endoplasmic reticulum (ER) in TANGO1 and HSP47 positive structures. Mass spectrometric analysis shows that DXM causes hyper-hydroxylation of proline and lysine residues on Collagen (COL1, COL3, COL4, COL5, COL7, COL12) and Latent-transforming growth factor beta-binding protein (LTBP1 and LTBP2) peptides coinciding with their secretion block. In addition, thermal proteome profiling of cells treated with DXM shows increased thermal stability of prolyl-hydroxylases such as P3H2, P3H3, P3H4, P4HA1 and P4HA2, suggesting a change in activity. Transcriptome analysis of pro-fibrotic stimulated NHLFs and hPCLS upon DXM treatment showed activation of an anti-fibrotic program via regulation of pathways such as those involved in the MMP-ADAMTS axis, WNT, and fibroblast-to-myofibroblast differentiation. Taken together, the data obtained from both in-vitro and ex-vivo models of fibrogenesis show that Dextromethorphan has potent anti-fibrotic activity by efficient inhibition of COL1 membrane trafficking in the ER.

cell biology↗

Halophilic nematodes live in America's Dead Sea

Extremophiles can reveal the origins of life on Earth and the possibility of life elsewhere. Most identified extremophiles are single-cell microbes, leaving gaps in our knowledge concerning the origins and habitable limits of multicellular organisms. Here, we report the recovery of roundworms (Phylum Nematoda) from the Great Salt Lake (GSL), UT, a hypersaline lake referred to as "Americas Dead Sea". Nematodes were found primarily in microbialites, benthic organosedimentary structures once abundant on early Earth. 16S sequencing of individual nematodes revealed a diverse bacterial community distinct from its surrounding habitat. Phylogenetic divergence compared to Owens Lake, another terminal lake in the Great Basin, suggests that GSL nematodes represent multiple previously undescribed species. These findings update our understanding of halophile ecosystems and the habitable limit of animals. One-Sentence SummaryWe report the discovery of novel halophilic nematodes in microbialites of the Great Salt Lake, UT.

ecology↗

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow

Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that hybrid neutrophils with dendritic features - including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation - accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils - which we identified in patient and murine glioblastomas - arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow - such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate - present therapeutic potential.

cancer biology↗

An alpaca-derived nanobody neutralizes the SARS-CoV-2 omicron variant

The SARS-CoV2 Omicron variant sub-lineages spread rapidly through the world, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for anti-SARS-CoV-2 agents that are effective against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production and potential for delivery via inhalation. Here, we characterize the RBD-specific nanobody W25, which we previously isolated from an alpaca, and show superior neutralization activity towards Omicron lineage BA.1 in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike surface glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. Furthermore, we show that W25 also binds the spike protein from the emerging, more infectious Omicron BA.2 lineage with picomolar affinity. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse prioritization of W25 for further clinical development.

microbiology↗

An ERAD-independent role for rhomboid pseudoprotease Dfm1 in mediating sphingolipid homeostasis

Nearly one-third of nascent proteins are initially targeted to the endoplasmic reticulum (ER) where they are correctly folded and assembled before being delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER-associated-degradation (ERAD) removes these clients from the ER membrane to the cytosol in a process known as retrotranslocation. Our recent work demonstrates that rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated integral membrane ERAD substrates. To survey for potential interaction partners of Dfm1, we performed protein-proximity labeling by BioID (proximity-dependent biotin identification) followed by mass spectrometry and identified several interacting proteins known to play a role in the sphingolipid biosynthesis pathway. Specifically, we found that Dfm1 physically interacts with the SPOTS complex, which is composed of serine palmitoyltransferase (SPT) enzymes and accessory components and is critical for catalyzing the first rate-limiting step of the sphingolipid biosynthesis pathway. We demonstrate for the first time that Dfm1 has a role in ER export, a function that is independent of Dfm1s canonical ERAD retrotranslocation function. Specifically, we show that loss of Dfm1 results in the accumulation of phosphorylated Orm2 at the ER, suggesting a novel role for Dfm1 in controlling Orm2 export from the ER and its subsequent degradation by EGAD. Moreover, recruitment of Cdc48 by Dfm1, which is critical for its role in ERAD retrotranslocation, is dispensable for Dfm1s role in ER export. Given that the accumulation of human Orm2 homologs, ORMDLs, are associated with many maladies, our study serves as a molecular foothold for understanding how dysregulation of sphingolipid metabolism leads to various diseases.

cell biology↗

Ontogeny of risk assessment and escape-hatching performance by red-eyed treefrog embryos in two threat contexts

Arboreal embryos of red-eyed treefrogs, Agalychnis callidryas, hatch prematurely in response to hypoxia when flooded and mechanosensory cues (MC) in snake attacks, but hatching later improves tadpole survival. We studied ontogenetic changes in risk assessment and hatching performance of embryos in response to flooding and physical disturbance. We hypothesized that risk assessment decreases as hatchling survival improves and hatching performance increases as embryos develop. Because snakes eat faster than embryos asphyxiate, we hypothesized that embryos decide to hatch sooner and hatch faster in response to MC. We video-recorded individual embryos hatching in response to each cue type, then compared the incidence and timing of a series of events and behaviors from cue onset to complete hatching across ages and stimuli. Latency from cue to hatching decreased developmentally in both contexts and was shorter with MC, but the elements contributing to those changes differed. Hypoxia-assessment involved position changes, which decreased developmentally along with assessment time. MC-assessment was passive, faster, and also decreased with age. The first stages of hatching, membrane rupture and head emergence, were surprisingly age-independent but faster with MC, congruent with greater effort under more immediate risk. In contrast, body emergence and compression showed ontogenetic improvement consistent with morphological constraints but no cue effect. Both appropriate timing and effective performance of hatching are necessary for continued development. Different stages of the process vary with development and environmental context, suggesting combinations of adaptive context- and stage-dependent behavior, cue-related constraints on information acquisition, and ontogenetic constraints on elements of performance. Summary statementDevelopment reduces risk assessment and improves hatching performance by red-eyed treefrog embryos in both flooding and simulated attacks. Predation cues elicit faster decisions and hatching, congruent with more immediate risk.

animal behavior and cognition↗

INRI-seq enables global cell-free analysis of translation initiation and off-target effects of antisense inhibitors

Ribosome profiling (Ribo-seq) is a powerful method for the transcriptome-wide assessment of protein synthesis rates and the study of translational control mechanisms. Yet, Ribo-seq also has limitations. These include difficulties with detection of low abundance transcripts and analysis of translation-modulating molecules such as antibiotics, which are often toxic or challenging to deliver into living cells. Here, we have developed in vitro Ribo-seq (INRI-seq), a cell-free method to analyze the translational landscape of a fully customizable synthetic transcriptome. Using Escherichia coli as an example, we show how INRI-seq can be used to analyze the translation initiation sites of a transcriptome of interest. We also study the global impact of direct translation inhibition by antisense peptide nucleic acid (PNA) to analyze PNA off-target effects. Overall, INRI-seq presents a scalable, sensitive method to study translation initiation in a transcriptome-wide manner without the potentially confounding effects of extracting ribosomes from living cells.

microbiology↗

Comprehensive analysis of PNA-based antisense antibiotics targeting various essential genes in uropathogenic Escherichia coli

Antisense peptide nucleic acids (PNAs) that target mRNAs of essential bacterial genes exhibit specific bactericidal effects in several microbial species, but our mechanistic understanding of PNA activity and their target gene spectrum is limited. Here, we present a systematic analysis of PNAs targeting eleven essential genes with varying expression levels in uropathogenic Escherichia coli (UPEC). We demonstrate that UPEC is susceptible to killing by peptide-conjugated PNAs, especially when targeting the widely-used essential gene acpP. Our evaluation yields three additional promising target mRNAs for effective growth inhibition, i.e., dnaB, ftsZ, and rpsH. The analysis also shows that transcript abundance does not predict target vulnerability and that PNA-mediated growth inhibition is not universally associated with target mRNA depletion. Global transcriptomic analyses further reveal PNA sequence-dependent but also -independent responses, including the induction of envelope stress response pathways. Importantly, we show that the growth inhibitory capacity of 9mer PNAs is generally as effective as their 10mer counterparts. Overall, our systematic comparison of a range of PNAs targeting mRNAs of different essential genes in UPEC suggests important features for PNA design, reveals a general bacterial response to PNA conjugates and establishes the feasibility of using PNA antibacterials to combat UPEC.

microbiology↗

Derlin Dfm1 Employs a Chaperone Function to Resolve Misfolded Membrane Protein Stress

Accumulation of misfolded proteins is a known source of cellular stress and can be detrimental to cellular health. While protein aggregation is a known hallmark of many diseases, the mechanisms by which protein aggregates cause toxicity and the molecular machines that prevent this toxicity are not completely understood. Here, we show that the accumulated misfolded membrane proteins form endoplasmic reticulum (ER) localized aggregates, impacting ubiquitin and proteasome homeostasis. Additionally, we have identified a chaperone ability of the yeast rhomboid pseudoprotease Dfm1 to influence solubilization of misfolded membrane proteins and prevent toxicity from misfolded membrane proteins. We establish that this function of Dfm1 does not require recruitment of the ATPase Cdc48 and it is distinct from Dfm1s previously identified function in dislocating misfolded membrane proteins to the cytosol for degradation.

cell biology↗

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. An amino acid residue in protein is represented as a single CG particle centered at the C atom position, while a nucleotide in RNA or DNA is modeled with three beads. Then, a single CG particle represents around ten heavy atoms in both proteins and nucleic acids. The input data in CG MD simulations are treated as GROMACS-style input files generated from a newly developed toolbox, GENESIS-CG-tool. To optimize the performance in CG MD simulations, we utilize multiple neighbor lists, each of which is attached to a different nonbonded interaction potential in the cell-linked list method. We found that random number generations for Gaussian distributions in the Langevin thermostat are one of the bottlenecks in CG MD simulations. Therefore, we parallelize the computations with message-passing-interface (MPI) to improve the performance on PC clusters or supercomputers. We simulate Herpes simplex virus (HSV) type 2 B-capsid and chromatin models containing more than 1,000 nucleosomes in GENESIS as examples of large-scale biomolecular simulations with residue-level CG models. This framework extends accessible spatial and temporal scales by multi-scale simulations to study biologically relevant phenomena, such as genome-scale chromatin folding or phase-separated membrane-less condensations. Author summaryMolecular dynamics (MD) simulations have been widely used to investigate biological phenomena that are difficult to study only with experiments. Since all-atom MD simulations of large biomolecular complexes are computationally expensive, coarse-grained (CG) models based on different approximations and interaction potentials have been developed so far. There are two practical issues in biological MD simulations with CG models. The first issue is the input file generations of highly heterogeneous systems. In contrast to well-established all-atom models, specific features are introduced in each CG model, making it difficult to generate input data for the systems containing different types of biomolecules. The second issue is how to improve the computational performance in CG MD simulations of heterogeneous biological systems. Here, we introduce a user-friendly toolbox to generate input files of residue-level CG models containing folded and disordered proteins, RNAs, and DNAs using a unified format and optimize the performance of CG MD simulations via efficient parallelization in GENESIS software. Our implementation will serve as a framework to develop novel CG models and investigate various biological phenomena in the cell.

biophysics↗