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Transcriptomic analysis of World Trade Center particulate Matter-induced pulmonary inflammation and drug treatments

Environment International 2023年 177卷 108027页

作者： Chen, Yun-Ti Li, Jinhui Chang, Jen-Ning Luo, Yong-Chun Yu, Wuyue Chen, Lung-Chi Yang, Jinn-Moon Institute of Bioinformatics and Systems Biology National Yang Ming Chiao Tung University Hsinchu30010 Taiwan Department of Chemistry and Chemical Biology Harvard University CambridgeMA02138 United States Department of Urology Stanford University Medical Center StanfordCA94304 United States Department of Environmental Medicine New York University School of Medicine New YorkNY10010 United States Degree Program of Applied Science and Technology National Yang Ming Chiao Tung University Hsinchu30010 Taiwan Department of Biological Science and Technology National Yang Ming Chiao Tung University Hsinchu30010 Taiwan Center for Intelligent Drug Systems and Smart Bio-devices National Yang Ming Chiao Tung University Hsinchu30010 Taiwan

Over 400,000 people are estimated to have been exposed to World Trade Center particulate matter (WTCPM) since the attack on the Twin Towers in Lower Manhattan on September 11, 2001. Epidemiological studies have found that exposure to dust may cause respiratory ailments and cardiovascular diseases. However, limited studies have performed a systematic analysis of transcriptomic data to elucidate the biological responses to WTCPM exposure and the therapeutic options. Here, we developed an in vivo mouse exposure model of WTCPM and administered two drugs (i.e., rosoxacin and dexamethasone) to generate transcriptomic data from lung samples. WTCPM exposure increased the inflammation index, and this index was significantly reduced by both drugs. We analyzed the transcriptomics derived omics data using a hierarchical systems biology model (HiSBiM) with four levels, including system, subsystem, pathway, and gene analyses. Based on the selected differentially expressed genes (DEGs) from each group, WTCPM and the two drugs commonly affected the inflammatory responses, consistent with the inflammation index. Among these DEGs, the expression of 31 genes was affected by WTCPM exposure and consistently reversed by the two drugs, and these genes included Psme2, Cldn18, and Prkcd, which are involved in immune- and endocrine-related subsystems and pathways such as thyroid hormone synthesis, antigen processing and presentation, and leukocyte transendothelial migration. Furthermore, the two drugs reduced the inflammatory effects of WTCPM through distinct pathways, e.g., vascular-associated signaling by rosoxacin, whereas mTOR-dependent inflammatory signaling was found to be regulated by dexamethasone. To the best of our knowledge, this study constitutes the first investigation of transcriptomics data of WTCPM and an exploration of potential therapies. We believe that these findings provide strategies for the development of promising optional interventions and therapies for airborne part

关键词： Dust

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Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex (vol 21, pg 120, 2018)

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NATURE NEUROSCIENCE 2018年第7期21卷 1017-1017页

作者： Hrvatin, Sinisa Hochbaum, Daniel R. Nagy, M. Aurel Cicconet, Marcelo Robertson, Keiramarie Cheadle, Lucas Zilionis, Rapolas Ratner, Alex Borges-Monroy, Rebeca Klein, Allon M. Sabatini, Bernardo L. Greenberg, Michael E. Department of Neurobiology Harvard Medical School Boston MA USA. Society of Fellows Harvard University Cambridge MA USA. Department of Neurobiology Howard Hughes Medical Institute Harvard Medical School Boston MA USA. Image and Data Analysis Core Harvard Medical School Boston MA USA. Department of Systems Biology Harvard Medical School Boston MA USA. Vilnius University Institute of Biotechnology Vilnius Lithuania. ICCB-L Single Cell Core Harvard Medical School Boston MA USA. Program for Bioinformatics and Integrative Genomics Graduate School of Arts and Science Division of Medical Sciences Harvard University Cambridge MA USA. Department of Neurobiology Howard Hughes Medical Institute Harvard Medical School Boston MA USA. bernardo_sabatini@hms.harvard.edu. Department of Neurobiology Harvard Medical School Boston MA USA. michael_greenberg@hms.harvard.edu.

Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.

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The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming

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细胞研究（英文版） 2012年第1期22卷 168-177页

作者： Athanasia D Panopoulos Oscar Yanes SergioRuiz Yasuyuki S Kida Dinh Diep Ralf Tautenhahn Aida Herrerias Erika M Batchelder Nongluk Plongthongkum Margaret Lutz W Travis Berggren Kun Zhang Ronald M Evans Gary Siuzdak Juan Carlos Izpisua Belmonte Gene Expression Laboratory The Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Stem Cell Core The Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Department of Bioengineering Institute for Genomic Medicine and Institute of Engineering in Medicine University of California at San Diego La Jolla CA 92093 USA Gene Expression Laboratory The Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Howard Hughes Medical Institute The Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Departments of Chemistry and Molecular Biology and Scripps Center for Metabolomics and Mass Spectrometry The Scripps Research Institute La Jolla CA 92037 USA Gene Expression Laboratory The Salk Institute for Biological Studies 10010 North Torrey Pines Road La Jolla CA 92037 USA Center of Regenerative Medicine in Barcelona Dr Aiguader 88 08003 Barcelona Spain Departments of Chemistry and Molecular Biology and Scripps Center for Metabolomics and Mass Spectrometry The Scripps Research Institute La Jolla CA 92037 USA Metabolomics Plaiform of the Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders(CIBERDEM) University Rovira i Virgili 43007 Tarragona Spain Bioinformatics and Systems Biology Graduate Program University of California at San Diego La Jolla CA 92093 USA Center of Regenerative Medicine in Barcelona Dr Aiguader 88 08003 Barcelona Spain

Metabolism is vital to every aspect of cell function, yet the metabolome of induced pluripotent stem cells (iPSCs) remains largely unexplored. Here we report, using an untargeted metabolomics approach, that human iPSCs share a pluripotent metabolomic signature with embryonic stem cells (ESCs) that is distinct from their parental cells, and that is characterized by changes in metabolites involved in cellular respiration. Examination of cellular bioenergetics corroborated with our metabolomic analysis, and demonstrated that somatic cells convert from an oxidative state to a glycolytic state in pluripotency. Interestingly, the bioenergetics of various somatic cells correlated with their reprogramming efficiencies. We further identified metabolites that differ between iPSCs and ESCs, which revealed novel metabolic pathways that play a critical role in regulating somatic cell reprogramming. Our findings are the first to globally analyze the metabolome of iPSCs, and provide mechanistic insight into a new layer of regulation involved in inducing pluripotency, and in evaluating iPSC and ESC equivalence.

关键词： reprogramming iPS cells metabolome stem cells metabolism

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Cheminformatics Tools for Analyzing and Designing Optimized Small Molecule Collections and Libraries

SSRN

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SSRN 2019年

作者： Moret, Nienke Clark, Nicholas A. Hafner, Marc Wang, Yuan Lounkine, Eugen Medvedovic, Mario Wang, Jinhua Gray, Nathanael Jenkins, Jeremy Sorger, Peter K. HMS LINCS and Druggable Genome Centers Laboratory of Systems Pharmacology Harvard Program in Therapeutic Science Harvard Medical School BostonMA02115 United States Department of Systems Biology Harvard Medical School BostonMA02115 United States Division of Biostatistics and Bioinformatics Department of Environmental Health University of Cincinnati CincinnatiOH45221 United States Novartis Institutes for BioMedical Research Inc. 181 Massachusetts Avenue CambridgeMA02139 United States Department of Cancer Biology Dana-Farber Cancer Institute BostonMA02115 United States Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School 360 Longwood Avenue Longwood Center 2209 BostonMA02115 United States Department of Bioinformatics and Computational Biology Genentech Inc. 1 DNA Way South San FranciscoCA94080 United States Warren Alpert 444 200 Longwood Avenue BostonMA02115 United States

Libraries of well-annotated small molecules have many uses in chemical genetics, drug discovery and drug repurposing. Many such libraries have become available, but few data-driven approaches exist to compare these libraries and design new ones. In this paper, we describe an approach to scoring and creating libraries based on available data, which is often incomplete, on binding selectivity, target coverage and induced cellular phenotypes as well as chemical structure, stage of clinical development and user preference. The approach, implemented as R software and a Web-accessible tool also assembles small sets of compounds (typically 2-8) that target a protein of interest while having the lowest possible off target overlap. Analysis of six kinase inhibitor libraries using our approach reveals dramatic differences among them, leading us to design a new LSP-OptimalKinase library that outperforms all previous collections in terms of target coverage and compact size. We also assemble a mechanism of action library that optimally covers 1852 targets of the liganded genome. Using our tools, individual research groups and companies can quickly analyze private compound collections, public libraries can be updated based on the latest data and the confounding effects of off-target activities minimized in chemical genetic studies. © 2019, The Authors. All rights reserved.

关键词： Libraries

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Successive responses of three coral holobiont components (coral hosts, symbiotic algae, and bacteria) to daily temperature fluctuations

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Ecological Indicators 2024年 158卷

作者： Hsieh, Yunli Eric Lu, Chih-Ying Liu, Po-Yu Kao, Jia-Min Yang, Sung-Yin Wu, Chien-Yi Wong, Jing-Wen Michelle Shikina, Shinya Fan, Tung-Yung Yang, Shan-Hua Systems Biology and Mathematical Modelling group Max Planck Institute of Molecular Plant Physiology Potsdam Germany Institute of Biochemistry and Biology Bioinformatics Department University of Potsdam Potsdam Germany School of BioSciences The University of Melbourne ParkvilleVIC Australia Molecular and Biological Agricultural Sciences Program Taiwan International Graduate Program National Chung Hsing University and Academia Sinica Taipei Taiwan Graduate Institute of Biotechnology National Chung Hsing University Taichung Taiwan Biodiversity Research Center Academia Sinica Taipei Taiwan School of Medicine College of Medicine National Sun Yat-sen University Kaohsiung Taiwan Institute of Fisheries Science National Taiwan University Taipei Taiwan Department of Aquatic Bioscience National Chiayi University Chiayi Taiwan Institute of Marine Environment and Ecology National Taiwan Ocean University Keelung Taiwan National Museum of Marine Biology and Aquarium Pingtung Taiwan

Corals and their associated microbiota form a "holobiont," which includes symbiotic algae and other associated microbiota dominated by bacteria. The composition of holobiont is influenced by various environmental factors, such as increasing sea water temperatures. Previous studies of the effects of temperature changes on coral physiology and associated bacterial communities have been conducted based on stable water temperatures set by mean temperatures, or by slowly increasing/decreasing temperatures. However, the daily temperature fluctuations that corals experience in nature are not stable. The current understanding of the effects of large daily temperature fluctuations on coral and associated bacterial community dynamics is limited. Hence, we conducted a four-week tank experiment using different large daily temperature fluctuations (±5 °C and ±7 °C) accompanied by continuous warming conditions (26 °C to 29 °C) to investigate the effects on two common reef-building corals, Stylophora pistillata and Pocillopora acuta. During the experiment, the activity of coral host catalase and superoxide dismutase were measured, the photosynthetic ability of symbiotic algae was recorded, and the variation in bacterial communities was analyzed using the V6-V8 region of 16S rDNA. According to the results, different parts of the holobionts of two coral species exhibited varying response rates to the continuous warming conditions and diurnal temperature fluctuations. Additionally, it was found that diurnal temperature fluctuations may mitigate the heat stress on the host and reduce the changes in bacterial response to warming. Therefore, it is suggested that the holobionts of different coral species may adopt different adaptation and survival strategies in response to diurnal temperature fluctuations and warming. Finally, based on the response of these two coral species under the conditions of diurnal temperature fluctuations and continuous warming, Acinetobacter and Rhodobacteracea

关键词： Temperature distribution

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The recency and geographical origins of the bat viruses ancestral to SARS-CoV and SARS-CoV-2

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Cell 2025年

作者： Pekar, Jonathan E. Lytras, Spyros Ghafari, Mahan Magee, Andrew F. Parker, Edyth Wang, Yu Ji, Xiang Havens, Jennifer L. Katzourakis, Aris Vasylyeva, Tetyana I. Suchard, Marc A. Hughes, Alice C. Hughes, Joseph Rambaut, Andrew Robertson, David L. Dellicour, Simon Worobey, Michael Wertheim, Joel O. Lemey, Philippe Institute of Ecology and Evolution University of Edinburgh Edinburgh United Kingdom Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla 92093 CA United States Department of Biomedical Informatics University of California San Diego La Jolla 92093 CA United States Department of Medicine University of California San Diego La Jolla 92093 CA United States Division of Systems Virology Department of Microbiology and Immunology The Institute of Medical Science The University of Tokyo Tokyo Japan Medical Research Council University of Glasgow Centre for Virus Research Glasgow United Kingdom Department of Biology University of Oxford Oxford United Kingdom Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles 90095 CA United States Department of Immunology and Microbiology The Scripps Research Institute La Jolla 92037 CA United States Institute of Genomics and Global Health Redeemer's University Osun State Ede Nigeria Department of Computer Science and Engineering University of California San Diego La Jolla 92093 CA United States Department of Mathematics School of Science and Engineering Tulane University New Orleans LA United States Department of Population Health and Disease Prevention University of California Irvine Irvine 92617 CA United States Department of Biostatistics Fielding School of Public Health University of California Los Angeles Los Angeles 90095 CA United States Department of Computational Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles 90095 CA United States School of Biological Sciences University of Hong Kong Hong Kong Hong Kong China Biodiversity Green Development Foundation Beijing China Spatial Epidemiology Lab (SpELL) Université Libre de Bruxelles CP160/12 50 av. FD Roosevelt Bruxelles 1050 Belgium Department of Microbiology Immunology and Transplantation Rega Institute

The emergence of SARS-CoV in 2002 and SARS-CoV-2 in 2019 led to increased sampling of sarbecoviruses circulating in horseshoe bats. Employing phylogenetic inference while accounting for recombination of bat sarbecoviruses, we find that the closest-inferred bat virus ancestors of SARS-CoV and SARS-CoV-2 existed less than a decade prior to their emergence in humans. Phylogeographic analyses show bat sarbecoviruses traveled at rates approximating their horseshoe bat hosts and circulated in Asia for millennia. We find that the direct ancestors of SARS-CoV and SARS-CoV-2 are unlikely to have reached their respective sites of emergence via dispersal in the bat reservoir alone, supporting interactions with intermediate hosts through wildlife trade playing a role in zoonotic spillover. These results can guide future sampling efforts and demonstrate that viral genomic regions extremely closely related to SARS-CoV and SARS-CoV-2 were circulating in horseshoe bats, confirming their importance as the reservoir species for SARS viruses. © 2025 The Authors

关键词： molecular epidemiology phylogeography sarbecoviruses virus evolution

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Phylogeographic and genetic network assessment of COVID-19 mitigation protocols on SARS-CoV-2 transmission in university campus residences

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eBioMedicine 2025年 116卷 105729-105729页

作者： Wertheim, Joel O. Vasylyeva, Tetyana I. Wood, Robert J. Cantrell, Kalen Contreras, Soraya Piña Feldheim, Aryeh Goyal, Ravi Havens, Jennifer L. Knight, Rob Laurent, Louise C. Moshiri, Niema Neuhard, Robert Sathe, Shashank Satterlund, Alysson Scioscia, Angela Song, Angela Y. Aigner, Stefan Andersen, Kristian G. Baer, Nathan A. Betty, Maryann Birmingham, Amanda Castro-Martinez, Anelizze Cheung, Willi De Hoff, Peter Fisch, Kathleen M. King, Alison J. Gangavarapu, Karthik Hakim, Abbas Henson, Benjamin Jepsen, Kristen Mac, Christina H. Ngo, Toan T. Nguyen, Kelly N. Ostrander, Tyler R. Perkins, Sarah Plascencia, Ashley Rivera, Andrea Rivera, Ariana Salido, Rodolfo A. Saucedo, Kieran C. Schwab, Madison Steedman, Allison L. Veder, Anthony Weiss, Alana Yeo, Gene W. Zeller, Mark Schooley, Robert T. Anderson, Cheryl M. Martin, Natasha K. Department of Medicine University of California San Diego La Jolla CA United States Department of Population Health and Disease Prevention University of California Irvine Irvine CA United States Herbert Wertheim School of Public Health and Human Longevity Science University of California San Diego La Jolla CA United States Department of Computer Science & Engineering University of California San Diego La Jolla CA United States Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla CA United States Department of Pediatrics University of California San Diego La Jolla CA United States Department of Bioengineering University of California San Diego La Jolla CA United States Department of Computer Science and Engineering University of California San Diego La Jolla CA United States Center for Microbiome Innovation University of California San Diego La Jolla CA United States Halıcıoğlu Data Science Institute University of California San Diego La Jolla CA United States Department of Obstetrics Gynecology and Reproductive Sciences University of California San Diego La Jolla CA United States Sanford Consortium of Regenerative Medicine University of California San Diego La Jolla CA United States University of California San Diego La Jolla CA United States

Background: Congregate living provides an ideal setting for SARS-CoV-2 transmission in which many outbreaks and superspreading events occurred. To avoid large outbreaks, universities turned to remote operations during the initial COVID-19 pandemic waves in 2020 and 2021. In late-2021, the University of California San Diego (UC San Diego) facilitated the return of students to campus with comprehensive testing, vaccination, masking, wastewater surveillance, and isolation policies. Methods: We performed molecular epidemiological and phylogeographic analysis of 4418 SARS-CoV-2 genomes sampled from UC San Diego students during the Omicron waves between December 2021 and September 2022, representing 58% of students with confirmed SARS-CoV-2 infection. We overlaid these analyses across on-campus residential information to assess the spread and persistence of SARS-CoV-2 within university residences. Findings: Within campus residences, SARS-CoV-2 transmission was frequent among students residing in the same room or suite. However, a quarter of pairs of suitemates with concurrent infections had distantly related viruses, suggesting separate sources of infection during periods of high incidence in the surrounding community. Students with concurrent infections residing in the same building were not at substantial increased probability of being members of the same transmission cluster. Genetic network and phylogeographic inference indicated that only between 3.1 and 12.4% of infections among students could be associated with transmission within buildings outside of individual suites. The only super-spreading event we detected was related to a large event outside campus residences. Interpretation: We found little evidence for sustained SARS-CoV-2 transmission within individual buildings, aside from students who resided in the same suite. Even in the face of heightened community transmission during the 2021–2022 Omicron waves, congregate living did not result in a heightened risk

关键词： Mitigation Phylogeography SARS-CoV-2 Transmission cluster University

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Array-Based High-Throughput Screening UNIT 5C.3 in Mouse Embryonic Stem Cells with shRNAs

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Current Protocols in Stem Cell biology 2013年第SUPPL.26期1卷 5C.3.1-5C.3.19页

作者： Wang, Chia-Hui Ma, Nianhan Lin, Yu-Tsen Wu, Cheng-Chung Wu, Hong-Jin Yu, Ching-Chia Hsiao, Michael Lu, Frank Leigh Schuyler, Scott C. Lu, Jean Genomics Research Center Academia Sinica Taipei Taiwan Institute of Systems Biology and Bioinformatics National Central University Taoyuan Taiwan Graduate Institute of Life Sciences National Defense Medical Center Taipei Taiwan Department of Pediatrics National Taiwan University Hospital and National Taiwan University Medical College Taipei Taiwan Department of Biomedical Sciences College of Medicine Chang Gung University Taoyuan County Taiwan Genomics and System Biology Program College of Life Science National Taiwan University Taipei Taiwan National Core Facility Program for Biotechnology National RNAi Platform Taipei Taiwan

High-throughput short-hairpin RNA (shRNA) lentivirus screening is a powerful tool for identifying multiple functional regulators in embryonic stem cells (ESCs). shRNA libraries can efficiently down-regulate target genes persistently with high efficiency. The concurrent measurement of relative cell number by alamarBlue (AB) assay and undifferentiated ESC markers via an alkaline phosphatase (ALP) activity assay in the same cell culture well provides an efficient and economical way to pinpoint factors crucial for ESC pluripotency and/or expansion. Most of the renewal pathways affect ALP activity. Thus, multiple positive and negative regulators can be identified by this method. In addition, morphological changes and/or the expression levels of specific pluripotency or differentiation markers examined by immunofluorescence can be used as secondary screens for target-gene selection. In summary, we describe an efficient way to identify multiple regulators of ESC renewal using shRNAs. © 2013 by John Wiley & Sons, Inc.

关键词： Embryonic stem cells High-throughput screening RNA interference Short-hairpin RNA

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Analyses of protein cores reveal fundamental differences between solution and crystal structures

arXiv

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arXiv 2019年

作者： Mei, Zhe Treado, John D. Grigas, Alex T. Levine, Zachary A. Regan, Lynne O'Hern, Corey S. Integrated Graduate Program in Physical & Engineering Biology Yale University New HavenCT06520 United States Department of Chemistry Yale University New HavenCT06520 United States Department of Mechanical Engineering & Materials Science Yale University New HavenCT06520 United States Graduate Program in Computational Biology & Bioinformatics Yale University New HavenCT06520 United States Department of Pathology Yale University New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Center for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

There have been several studies suggesting that protein structures solved by NMR spectroscopy and x-ray crystallography show significant differences. To understand the origin of these differences, we assembled a database of high-quality protein structures solved by both methods. We also find significant differences between NMR and crystal structures|in the root-mean-square deviations of the Cα atomic positions, identities of core amino acids, backbone and sidechain dihedral angles, and packing fraction of core residues. In contrast to prior studies, we identify the physical basis for these differences by modelling protein cores as jammed packings of amino-acid-shaped particles. We find that we can tune the jammed packing fraction by varying the degree of thermalization used to generate the packings. For an athermal protocol, we find that the average jammed packing fraction is identical to that observed in the cores of protein structures solved by x-ray crystallography. In contrast, highly thermalized packing-generation protocols yield jammed packing fractions that are even higher than those observed in NMR structures. These results indicate that thermalized systems can pack more densely than athermal systems, which suggests a physical basis for the structural differences between protein structures solved by NMR and x-ray crystallography. Copyright © 2019, The Authors. All rights reserved.

关键词： X ray crystallography

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Using physical features of protein core packing to distinguish real proteins from decoys

arXiv

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arXiv 2020年

作者： Grigas, Alex T. Mei, Zhe Treado, John D. Levine, Zachary A. Regan, Lynne O'Hern, Corey S. Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Department of Chemistry Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Pathology Yale University New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Institute of Quantitative Biology Biochemistry and Biotechnology Centre for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

The ability to consistently distinguish real protein structures from computationally generated model decoys is not yet a solved problem. One route to distinguish real protein structures from decoys is to delineate the important physical features that specify a real protein. For example, it has long been appreciated that the hydrophobic cores of proteins contribute signifficantly to their stability. As a dataset of decoys to compare with real protein structures, we studied submissions to the bi-annual CASP competition (speciffically CASP11, 12, and 13), in which researchers attempt to predict the structure of a protein only knowing its amino acid sequence. Our analysis reveals that many of the submissions possess cores that do not recapitulate the features that define real proteins. In particular, the model structures appear more densely packed (because of energetically unfavorable atomic overlaps), contain too few residues in the core, and have improper distributions of hydrophobic residues throughout the structure. Based on these observations, we developed a deep learning method, which incorporates key physical features of protein cores, to predict how well a computational model recapitulates the real protein structure without knowledge of the structure of the target sequence. By identifying the important features of protein structure, our method is able to rank decoys from the CASP competitions equally well, if not better than, state-of-the-art methods that incorporate many additional features. Copyright © 2020, The Authors. All rights reserved.

关键词： Proteins

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