Biology subjects

Hwang, H.

Publications and source records attributed to Hwang, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Engineering Methyl-Coenzyme M Reductase for Enhanced Methane and Carbon Dioxide Capture through Biofilm Growth

Methane is a potent greenhouse gas, nearly half of which is consumed anaerobically by anaerobic methanotrophic archaea (ANME) through methyl-coenzyme M reductase (Mcr). However, ANME cannot be grown as pure cultures, and obtaining active ANME Mcr in vitro remains extremely challenging, preventing previous efforts to engineer this key enzyme. Here, we used directed evolution in the methanogen Methanosarcina acetivorans to enhance ANME-1 Mcr (McrANME-1) activity for methane and carbon dioxide capture by selecting McrANME-1 variants with improved growth during methane-dependent cultivation. As a result, we discovered two beneficial substitutions in the catalytic -subunit of McrANME-1, S60P and I154V, that increased biofilm growth as well as acetate production and methane capture. AlphaFold structural predictions suggest possible mechanistic explanations for these beneficial substitutions. These findings demonstrate that Mcr can be engineered to enhance methane and carbon dioxide capture, establishing a foundation for biological greenhouse gas mitigation and carbon utilization technologies.

Synthetic Biology↗

bioRxiv2026

Maternal age modulates progeny social behavior via a small RNA-neuropeptide axis

Parental age influences offspring traits across species, yet the molecular pathways by which maternal state modulates progeny neural function remain poorly defined. Here we demonstrate that maternal age in C. elegans regulates progeny avoidance of the social pheromone by modulating the activity of a defined sensory circuit. Progeny of young mothers exhibit stronger activity of the pheromone-sensing ADL neurons and enhanced pheromone avoidance, whereas progeny of old mothers display reduced neuronal responses and weaker repulsion. We identify an ERI-1-microRNA-neuropeptide signaling axis operating in peptidergic AVH interneurons that modulates ADL circuit responsiveness. ERI-1 promotes expression of the neuropeptide gene flp-26 by repressing mir-8207, and signaling from AVH to ADL establishes pheromone sensitivity. Maternal aging is associated with reduced ERI-1 expression in progeny AVH neurons and dampening this signaling pathway. Consequently, progeny of young mothers, though developmentally less robust, disperse more readily from crowded, pheromone-rich environments, offsetting their early-life disadvantages. Our findings reveal a molecular and circuit-level mechanism by which maternal physiology adaptively configures offspring neural computation and behavioral strategy across generations.

neuroscience↗

bioRxiv2026

Results of a large scale study of the binding of 50 type IIinhibitors to 348 kinases: The role of protein reorganization

Kinase family proteins constitute the second largest protein class targeted in drug development efforts, most prominently to treat cancer, but also several other diseases associated with kinase dysfunction. In this work we focus on type II kinase inhibitors which bind to the "classical" inactive conformation of the protein kinase catalytic domain where the DFG motif has a "DFG-out" orientation and the activation loop is folded. Many Tyrosine kinases (TKs) exhibit strong binding affinity with a wide spectrum of type II inhibitors while serine/threonine kinases (STKs) often bind more weakly. Recent work suggests this difference is largely due to differences in the folded to extended conformational equilibrium of the activation loop between TKs vs. STKs. The binding affinity of a type II inhibitor to its kinase target can be decomposed into a sum of two contributions: (1) the free energy cost to reorganize the protein from the active to inactive state, and (2) the binding affinity of the type II inhibitor to the inactive kinase conformation. In previous work we used a Potts statistical energy potential based on sequence co-variation to thread sequences over ensembles of active and inactive kinase structures. The threading function was used to estimate the free energy cost to reorganize kinases from the active to classical inactive conformation, and we showed that this estimator is consistent with the results of molecular dynamics free energy simulations for a small set of STKs and TKs. In the current study, we analyze the results of a large-scale study of the binding affinities of 50 type II inhibitors to 348 kinases, of which the results for 16 of the 50 type II inhibitors were reported in an earlier study (the "Davis dataset"); the binding data for the remaining 34 type II inhibitors to the panel of 348 kinases were recently obtained (the "Schrodinger dataset"). We use the Potts statistical energy model to investigate the contribution of protein reorganization to the selectivity of the large kinase panel against the set of 50 type II inhibitors, and find that protein reorganization makes a significant contribution to the selectivity. The AUC of the receiver-operator characteristic curve is [~]0.8. We report the results of an internal "blind test", that shows how Potts threading energies can provide more accurate estimates of kinase selectivity than corresponding predictions using experimental results of small sample size. We discuss why two STK phylogenetic kinase families, STE and CMGC, appear to contain many outliers, and how to improve the ability to predict kinase selectivity with a more complete analysis of the kinase conformational landscape. We compare the performance of Potts threading for predicting binding properties of the large set of (50) Type II inhibitors to 348 kinases, with those of a sequence-based purely machine learning model, DeepDTAGen, a publicly available machine learning model that was trained on the complete Davis dataset, including both Type I and Type II kinase inhibitors. We observe that DeepDTAGen performs well on binding predictions for the 16 type II inhibitors in the Davis dataset, but performs poorly on binding predictions for the 34 type II inhibitors against 348 kinases in the Schrodinger dataset.

biophysics↗

bioRxiv2026

Mechanistic Language Modeling and Oxygenated 3D Screening Reveal Berberine and Enzalutamide Synergy in Resistant Prostate Cancer

Resistance to androgen receptor inhibitors remains a primary challenge in prostate cancer treatment, yet identifying synergis-tic co-therapies is hindered by immense combinatorial search spaces and the limited interpretability of predictive computation models. Here, we developed an integrated discovery-validation axis coupling knowledge-augmented large language models with oxygen-supplemented 3D spheroid assays. By leveraging inherent model stochasticity, our framework measures the degree of consensus across independent predictions to establish a formal metric for predictive accuracy. This principle enables high-throughput assessment of complex signaling crosstalk, yielding mechanistic rationales for all predictions and defining a high-confidence zone that minimizes experimental attrition. Utilizing this approach to screen 3,592 natural products, we identified a previously unrecognized synergy between berberine and enzalutamide that re-sensitizes resistant cells. Validation confirms that berberine perturbs the PI3K/AKT/mTOR and AMPK axes, a finding consistent with the mechanistic rationales computationally derived by the framework. Integrating interpretable AI with physiologically relevant 3D screening provides a scalable methodology for the rational discovery of synergistic therapies. SignificanceIntegrating mechanistic AI with oxygenated 3D screening, we identify a novel berberine-enzalutamide synergy. This framework resolves complex signaling dependencies, providing a scalable, transparent methodology for the rational discovery of effective combination therapies.

bioengineering↗

bioRxiv2025

Identification of Small Molecule Dimethyoxyphenyl Piperazine Inhibitors of Alpha-Synuclein Fibril Growth

Identification of Small Molecule Dimethyoxyphenol Piperazine Inhibitors of Alpha-Synuclein Fibril Growth Alpha-synuclein (asyn) fibril accumulation is the defining feature of Parkinson disease and is a target for disease-modifying treatments. One therapeutic strategy to reduce fibril accumulation is inhibition of asyn fibril growth. We developed a sensitive fluorescence-based fibril growth assay to screen for small molecule inhibitors. After validating the inhibition assay using a previously identified inhibitor, epigallocatechin-3-gallate, we identified compound 1 as a lead for inhibition of fibril growth. We analysed structure-activity relationships with analogs of 1 to optimize inhibition potency. Our results identified two dimethoxyphenyl piperazine analogs with more potent inhibition of in-vitro assembled fibrils. These analogs also inhibited the growth of asyn fibrils amplified from Lewy Body Disease brain tissue, further validating the inhibitor screening assay. Molecular docking studies indicate that these compounds can bind to the fibril ends, suggesting a potential capping mechanism through which these compounds inhibit the sequential association of monomeric asyn required for fibril growth.

neuroscience↗

bioRxiv2025

Serum Lewis fucosylation reports on survivorship of patients with septic shock upon admission to intensive care unit

Septic shock, the excessive immune response to pathogen infection, poses a major health concern accounting globally for [~]20% of all deaths. Current methods to establish disease severity are unacceptably slow, unspecific and insensitive, hindering timely and effective treatment. Aiming to identify easy-to-assay glyco-signatures that may identify and guide the clinical management of the most critically unwell patients, we applied quantitative glycomics and glycoproteomics to sera longitudinally collected from septic shock survivors (n=29) and non-survivors (n=8). Glycomics of all 134 serum samples (sampled daily until recovery/death) revealed significant N-glycome dynamics across both patient groups. Unsupervised clustering of the serum N-glycome upon ICU admission (day 1) indicated survivorship-specific glyco- signatures. We therefore employed machine learning to train a random forest model using the serum N-glycome data. The model accurately classified survivorship outcomes of 35 of 37 patients (specificity 94.6%) and correctly predicted 6 of 8 non-survivors (sensitivity 75%) based on ICU day 1 data. Further interrogation of the serum N-glycome data revealed elevated Lewis fucosylation in non-survivors relative to survivors at ICU admission, a finding recapitulated by glycoproteomics. Amongst 58 other serum proteins strongly linked to acute phase response and stress pathways, alpha-1-acid-glycoprotein was identified as a principal carrier of Lewis fucosylation with a potential to stratify septic shock survivors from non- survivors (AUC 0.935). This study lays a foundation for risk stratification of septic shock patients by uncovering easy-to-assay glyco-signatures that identify individuals with poor survival outcomes upon ICU admission, with the potential to translate to early individualised clinical care at the bedside.

biochemistry↗

bioRxiv2025

Idebenone Enhances the Early Microglial Response to Traumatic Brain Injury and Mitigates Acute Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways

Traumatic Brain Injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology panel to test the hypothesis that idebenone post-treatment mitigates TBI pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in peri-lesional cortex at 24 hours post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology:biological process (GO:BP) pathways "ephrin receptor signaling" and "dopamine metabolic process." Gene co-expression analysis correlated levels of microglial complement component 1q (C1q) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, results suggest that idebenone enhances TBI-induced microglial proliferation within the first 24 hours of TBI and identify Ephrin-A and dopamine signaling as novel idebenone targets.

neuroscience↗

bioRxiv2025

Multiomic profiling of hypoxic glioblastoma stem cells reveals expansion of subpopulations with distinct epigenetic and CNV profiles

Glioblastoma is characterized by extensive intratumoral heterogeneity driven by dynamic mi-croenvironmental cues such as hypoxia. While transcriptional and epigenetic variability have been separately linked to hypoxia responses, the integrated impact of hypoxia on gene regulation and clonal architecture in glioblastoma stem cells (GSCs) remains poorly defined. We applied singlenucleus multi-omics--integrating RNA-seq and ATAC-seq--to patient-derived GSCs cultured under normoxic or hypoxic conditions. This enabled simultaneous profiling of gene expression and chromatin accessibility within the same cells. Transcription factor (TF) regulatory networks were inferred using Dictys, while RNA-chromatin dynamics were modeled with MultiVelo. Clonal structure and copy number variations (CNVs) were resolved at single-cell resolution using RIDDLER on snATAC-seq data. Hypoxia induced the emergence of four distinct GSC subpopulations with unique transcriptomic and epigenetic profiles enriched for mesenchymal, angiogenic, and proliferative signatures. Regulatory network modeling revealed novel hypoxia-associated TFs--SP2, CREM, and ETV3--that modulate downstream oncogenic pathways. Trajectory analysis uncovered hypoxia-driven reversals in RNA-chromatin coupling, revealing dysregulated future transcriptional states of key genes such as MMP16 and SVIL. CNV profiling identified 13 clonal substructures, with specific clones (e.g., 5, 6, 9) selectively enriched under hypoxia and harboring distinct chromosomal alterations. These results demonstrate coordinated remodeling of GSC gene regulation and clonal fitness in response to hypoxic stress. Our findings reveal that hypoxia drives concurrent epigenetic, transcriptomic, and clonal selection in glioblastoma stem cells. This integrated model of hypoxia-induced plasticity provides mechanistic insights into tumor adaptation and identifies novel regulators that may serve as targets for therapeutic intervention in the hypoxic niche of glioblastoma.

cancer biology↗

bioRxiv2025

Targeting Monoallelic CREBBP/EP300 Mutations in Germinal Center-Derived B-Cell Lymphoma with a First-in-Class Histone Acetyltransferase Activator

Germinal center B-cell lymphomas frequently exhibit monoallelic loss-of-function mutations in the histone acetyltransferases CREBBP and p300, which contribute to lymphoma development, disrupt normal germinal center biology, and promote immune evasion. This study evaluates YF2, a histone acetyltransferase activator that increases CREBBP/p300 activity, as a potential therapeutic approach for B-cell lymphoma. YF2 binds the bromodomain of CREBBP/p300, increasing their auto-acetylation and enzymatic activity. It also induces cytotoxicity in B-cell lymphoma cell lines, with a stronger response in those carrying CREBBP/EP300 mutations. Additionally, YF2 increases the acetylation of key CREBBP/p300 substrates, including H3K27, p53, and BCL6, leading to enhanced apoptosis and altered B-cell diTerentiation. YF2 is well tolerated in vivo and extends survival in both cell line- and patient-derived xenograft mouse models. Moreover, YF2 exposure upregulates antigen-presentation markers and reshapes the immune microenvironment, strengthening responses to immune checkpoint blockade. Taken together, these findings support pharmacologic activation of CREBBP/p300 with YF2 as a compelling therapeutic strategy for B-cell lymphoma. SignificanceYF2 stimulates CREBBP/p300 activity to normalize B-cell diTerentiation and enhance immune recognition, oTering a potential approach to limit lymphoma progression and strengthen immunotherapy responses.

cancer biology↗

bioRxiv2024

Evolutionary unique N-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in Cryptococcus neoformans

A conserved N-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system has evolved in eukaryotes to ensure accuracy during glycoprotein folding. The human pathogen Cryptococcus neoformans possesses a unique N-glycosylation pathway that affects microbial physiology and interactions with the infected host. To investigate the molecular features and functions of the ERQC system in C. neoformans, we characterized a set of mutants with deletion of genes coding for the ERQC sensor UDP-glucose:glycoprotein glucosyltransferase (UGG1) and putative 1,2-mannose-trimming enzymes (MNS1, MNS101, MNL1, and MNL2). The ugg1{Delta}, mns1{Delta}, mns101{Delta}, and mns1{Delta}101{Delta} mutants showed alterations in N-glycan profiles, defective cell surface organization, decreased survival in host cells, and varying degrees of reduced in vivo virulence. The ugg1{Delta} strain exhibited severely impaired extracellular secretion of capsular polysaccharides and virulence-related enzymes. Comparative transcriptome analysis showed the upregulation of protein folding, proteolysis, and cell wall remodeling genes, indicative of induced ER stress. However, no apparent changes were observed in the expression of genes involved in protein secretion or capsule biosynthesis. Additionally, extracellular vesicle (EV) analysis combined with proteomic analysis showed significant alterations in the number, size distribution, and cargo composition of EVs in ugg1{Delta}. These findings highlight the essential role of the functional ERQC system for cellular fitness under adverse conditions and proper EV-mediated transport of virulence factors, which are crucial for the full fungal pathogenicity of C. neoformans.

microbiology↗

bioRxiv2024

Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia

Reproductive status influences metabolism and health across lifespan in diverse ways and mitochondrial function playing a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPAR, but not DAF-16/FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.

genetics↗

bioRxiv2024

Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.

neuroscience↗

bioRxiv2024

PIEZO acts in an intestinal valve to regulate swallowing in C. elegans

Sensations of the internal state of the body play crucial roles in regulating the physiological processes and maintaining homeostasis of an organism. However, our understanding of how internal signals are sensed, processed, and integrated to generate appropriate biological responses remains limited. Here, we show that the C. elegans PIEZO channel, encoded by pezo-1, regulates food movement in the intestine by detecting food accumulation in the anterior part of the intestinal lumen, thereby triggering rhythmical movement of the pharynx, referred to as the pharyngeal plunge. pezo-1 deletion mutants exhibit defects in the pharyngeal plunge, which is rescued by PEZO-1 or mouse PIEZO1 expression, but not by PIEZO2, in a single isolated non-neuronal tissue of the digestive tract, the pharyngeal-intestinal valve. Genetic ablation or optogenetic activation of this valve inhibits or induces the pharyngeal plunge, respectively. Moreover, pressure built in the anterior lumen of the intestine results in a pezo-1-dependent pharyngeal plunge, which is driven by head muscle contraction. These findings illustrate how interoceptive processes in a digestive organ regulate swallowing through the PIEZO channel, providing insights into how interoception coordinates ingestive processes in higher animals, including humans.

neuroscience↗

bioRxiv2024

Dzip1 is dynamically expressed in the vertebrate germline and regulates the development of Xenopus primordial germ cells.

Primordial germ cells (PGCs) are the precursors of sperms and oocytes. Proper development of PGCs is crucial for the survival of the species. In many organisms, factors responsible for PGC development are synthesized during early oogenesis and assembled into the germ plasm. During early embryonic development, germ plasm is inherited by a few cells, leading to the formation of PGCs. While germline development has been extensively studied, how components of the germ plasm regulate PGC development is not fully understood. Here, we report that Dzip1 is dynamically expressed in vertebrate germline and is a novel component of the germ plasm in Xenopus and zebrafish. Knockdown of Dzip1 impairs PGC development in Xenopus embryos. At the molecular level, Dzip1 physically interacts with Dazl, an evolutionarily conserved RNA-binding protein that plays a multifaced role during germline development. We further showed that the sequence between amino acid residues 282 and 550 of Dzip1 is responsible for binding to Dazl. Disruption of the binding between Dzip1 and Dazl leads to defective PGC development. Taken together, our results presented here demonstrate that Dzip1 is dynamically expressed in the vertebrate germline and plays a novel function during Xenopus PGC development.

developmental biology↗

bioRxiv2024

Differential functions of the dorsal and intermediate regions of the hippocampus for optimal goal-directed navigation in VR space

Goal-directed navigation requires the hippocampus to process spatial information in a value-dependent manner, but its underlying mechanism needs to be better understood. Here, we investigated whether the dorsal (dHP) and intermediate (iHP) regions of the hippocampus differentially function in processing place and its associated value information. Rats were trained in a place-preference task involving reward zones with different values in a visually rich VR environment where two-dimensional navigation was possible. Rats learned to use distal visual scenes effectively to navigate to the reward zone associated with a higher reward. Inactivation of both dHP and iHP with muscimol altered the efficiency and precision of wayfinding behavior, but iHP inactivation induced more severe damage, including impaired place preference. Our findings suggest that the iHP is more critical for value-dependent navigation toward higher-value goal locations.

neuroscience↗

bioRxiv2023

Phase transition of maternal RNAs during vertebrate oocyte-to-embryo transition

The oocyte-to-embryo transition (OET) is regulated by maternal products stored in the oocyte cytoplasm, independent of transcription. How maternal products are precisely remodeled to dictate the OET remains an open question. In this work, we discover the dynamic phase transition of maternal RNAs during Xenopus OET. We have identified 863 maternal transcripts that transition from a soluble state to a detergent-insoluble one after oocyte maturation. These RNAs are enriched in the animal hemisphere and many of them encode key cell cycle regulators. In contrast, 165 transcripts, including nearly all Xenopus germline RNAs and some vegetally localized somatic RNAs, undergo an insoluble-to-soluble phase transition. This phenomenon is conserved in zebrafish. Our results demonstrate that the phase transition of germline RNAs influences their susceptibility to RNA degradation machinery and is mediated by the remodeling of germ plasm. This work thus uncovers novel remodeling mechanisms that act on RNAs to regulate vertebrate OET.

developmental biology↗

bioRxiv2022

The metabolite alpha-ketobutyrate increases health and life spans by activating AMPK

Aging is a complex process that is directly related to human health and disease. The extraordinary finding that aging is malleable, as shown in model organisms whose life and health spans are extended by specific gene mutations or dietary or pharmacological perturbations 1-3, has offered enormous hope for our understanding and treatment of aging and related diseases. Although many molecules have been identified that can extend the lifespan of model organisms, few have been shown to alleviate age-related symptoms or illness in mammals 4. Here we show that supplementation with the endogenous metabolite -ketobutyrate (-KB) increases the lifespan of adult C. elegans. Using Gelfree DARTS-PROTOMAP, we identified microtubule-actin cross-linking factor (MACF1) that was protected against proteolysis in the presence of -KB. MACF1 belongs to the spectraplakin family of giant, evolutionarily conserved proteins with versatile functions 5, but their link to longevity regulation has not been explored. -KBs longevity effect in C. elegans is abrogated by loss-of-function mutation in vab-10, encoding the worm ortholog of mammalian MACF1 6. Like -KB treatment, vab-10 knockdown activates AMP-activated protein kinase (AMPK), and AMPK is required for -KB effects on longevity. The findings suggest a model in which -KB increases longevity by activating AMPK via VAB-10/MACF1 modulation. -KB also delays aging in mammals, increasing the lifespan of aged male mice and the healthspan of both male and female animals. Targeting of broadly expressed scaffolding proteins in connection to cellular energy homeostasis seems to be a clever way that nature has devised for metabolite signals to impinge upon multiple organ and tissue systems, which may have utility for controlling aging and related diseases.

physiology↗

bioRxiv2022

PrePCI: A structure- and chemical similarity-informed database of predicted protein compound interactions

We describe the Predicting Protein Compound Interactions (PrePCI) database which comprises over 5 billion predicted interactions between nearly 7 million chemical compounds and 19,797 human proteins. PrePCI relies on a proteome-wide database of structural models based on both traditional modeling techniques and the AlphaFold Protein Structure Database. Sequence and structural similarity-based metrics are established between template proteins in the Protein Data Bank, T, that bind small molecules, C, and proteins in the models database, Q. When these metrics pass a sequence threshold value, it is assumed that C also binds to Q with a probability derived from machine learning. If the relationship is based on structure, this probability is based on a scoring function that measures the extent to which C is compatible with the binding site of Q as described in the LT-scanner algorithm. For every predicted complex derived in this way, chemical similarity based on the Tanimoto Coefficient identifies other small molecules that may bind to Q. A likelihood ratio for the binding of C to Q is obtained from naive Bayesian statistics. The PrePCI algorithm performs well under different validations. It can be queried by entering a UniProt ID for a protein and obtaining a list of compounds predicted to bind to it along with associated probabilities. Alternatively, entering an identifier for the compound outputs a list of proteins it is predicted to bind. Specific applications of the database are described and a strategy is introduced to use PrePCI as a first step in a docking screen.

systems biology↗