Publications by authors named "Jiye Shi"

160 Publications

Modulating Target Protein Biology Through the Re-mapping of Conformational Distributions Using Small Molecules.

Front Chem 2021 4;9:668186. Epub 2021 May 4.

UCB Pharma, Slough, United Kingdom.

Over the last 10 years considerable progress has been made in the application of small molecules to modulating protein-protein interactions (PPIs), and the navigation from "undruggable" to a host of candidate molecules in clinical trials has been well-charted in recent, comprehensive reviews. Structure-based design has played an important role in this scientific journey, with three dimensional structures guiding medicinal chemistry efforts. However, the importance of two additional dimensions: movement and time is only now being realised, as increasing computing power, closely aligned with wet lab validation, is applied to the challenge. Protein dynamics are fundamental to biology and disease, and application to PPI drug discovery has massively widened the scope for new chemical entities to influence function from allosteric, and previously unreported, sites. In this forward-looking perspective we highlight exciting, new opportunities for small molecules to modulate disease biology, by adjusting the frequency profile of natural conformational sampling, through the stabilisation of clinically desired conformers of target proteins.
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http://dx.doi.org/10.3389/fchem.2021.668186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129178PMC
May 2021

A nano-integrated microfluidic biochip for enzyme-based point-of-care detection of creatinine.

Chem Commun (Camb) 2021 May;57(38):4726-4729

Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201800, P. R. China. and University of Chinese Academy of Sciences, Beijing 100049, P. R. China and Institute of Molecular Medicine, Renji Hospital, School of Medicine and School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200127, P. R. China.

A nano-integrated portable enzymatic microfluidic electrochemical biochip was developed for single-step point-of-care testing of creatinine. The biochip could automatically eliminate a lot of interferences from practical biological samples and enzymatic intermediate products. Gold nanostructure- and carbon nanotube-based screen-printed carbon electrodes were integrated into microfluidic structures to improve the detection performance for creatinine. The microfluidic electrochemical biochip holds promise to become a practical device for medical diagnosis, especially POCT.
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http://dx.doi.org/10.1039/d1cc00825kDOI Listing
May 2021

Multichannel Immunosensor Platform for the Rapid Detection of SARS-CoV-2 and Influenza A(H1N1) Virus.

ACS Appl Mater Interfaces 2021 May 9;13(19):22262-22270. Epub 2021 May 9.

Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, P. R. China.

The coronavirus disease 2019 (COVID-19) can present a similar syndrome to an influenza infection, which may complicate diagnosis and clinical management of these two important respiratory infectious diseases, especially during the peak season of influenza. A rapid and convenient point-of-care test (POCT) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus is of great importance for prompt and efficient control of these respiratory epidemics. Herein, a multichannel electrochemical immunoassay (MEIA) platform was developed based on a disposable screen-printed carbon electrode (SPCE) array for the on-site detection of SARS-CoV-2 and A(H1N1). The developed MEIA was constructed with eight channels and allowed rapid detection on a single array. On the SPCE surface, monoclonal antibodies against influenza A(H1N1) hemagglutinin (HA) protein or SARS-CoV-2 spike protein were coated to capture the target antigens, which then interacted with a horseradish peroxidase (HRP)-labeled detection antibody to form an immuno-sandwich complex. The results showed that the MEIA exhibited a broader linear range than ELISA and comparable sensitivity for A(H1N1) HA and SARS-CoV-2 spike protein. The detection results on 79 clinical samples for A(H1N1) suggested that the proposed MEIA platform showed comparable results with ELISA in sensitivity (with a positive rate of 100% for positive samples) but higher specificity, with a false-positive rate of 5.4% for negative samples versus that of 40.5% with ELISA. Thus, it offers great potential for the on-the-spot differential diagnosis of infected patients, which would significantly benefit the efficient control and prevent the spread of these infectious diseases in communities or resource-limited regions in the future.
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http://dx.doi.org/10.1021/acsami.1c05770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130191PMC
May 2021

Programming cell communications with pH-responsive DNA nanodevices.

Chem Commun (Camb) 2021 May;57(37):4536-4539

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China.

DNA nanoswitches on cell surfaces could respond to changes of pH under physiological conditions by switching from a three-chain structure to a double-chain structure, thus connecting another set of cells modified with complementary single-stranded DNA. This pH-triggered cell communication offers a promising approach for cell-based therapy under a tumor microenvironment.
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http://dx.doi.org/10.1039/d1cc00875gDOI Listing
May 2021

The Promise of AI for DILI Prediction.

Front Artif Intell 2021 14;4:638410. Epub 2021 Apr 14.

LIT AI Lab, Johannes Kepler University Linz, Linz, Austria.

Drug-induced liver injury (DILI) is a common reason for the withdrawal of a drug from the market. Early assessment of DILI risk is an essential part of drug development, but it is rendered challenging prior to clinical trials by the complex factors that give rise to liver damage. Artificial intelligence (AI) approaches, particularly those building on machine learning, range from random forests to more recent techniques such as deep learning, and provide tools that can analyze chemical compounds and accurately predict some of their properties based purely on their structure. This article reviews existing AI approaches to predicting DILI and elaborates on the challenges that arise from the as yet limited availability of data. Future directions are discussed focusing on rich data modalities, such as 3D spheroids, and the slow but steady increase in drugs annotated with DILI risk labels.
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http://dx.doi.org/10.3389/frai.2021.638410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080874PMC
April 2021

Biocomputing Based on DNA Strand Displacement Reactions.

Chemphyschem 2021 Jun 20;22(12):1151-1166. Epub 2021 May 20.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 201240, China.

The high sequence specificity and precise base complementary pairing principle of DNA provides a rich orthogonal molecular library for molecular programming, making it one of the most promising materials for developing bio-compatible intelligence. In recent years, DNA has been extensively studied and applied in the field of biological computing. Among them, the toehold-mediated strand displacement reaction (SDR) with properties including enzyme free, flexible design and precise control, have been extensively used to construct biological computing circuits. This review provides a systemic overview of SDR design principles and the applications. Strategies for designing DNA-only, enzymes-assisted, other molecules-involved and external stimuli-controlled SDRs are described. The recently realized computing functions and the application of DNA computing in other fields are introduced. Finally, the advantages and challenges of SDR-based computing are discussed.
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http://dx.doi.org/10.1002/cphc.202100140DOI Listing
June 2021

Membrane Interactions of α-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.

J Phys Chem B 2021 03 15;125(11):2929-2941. Epub 2021 Mar 15.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.

α-Synuclein (αS) is a presynaptic protein that binds to cell membranes and is linked to Parkinson's disease (PD). Binding of αS to membranes is a likely first step in the molecular pathophysiology of PD. The αS molecule can adopt multiple conformations, being largely disordered in water, adopting a β-sheet conformation when present in amyloid fibrils, and forming a dynamic multiplicity of α-helical conformations when bound to lipid bilayers and related membrane-mimetic surfaces. Multiscale molecular dynamics simulations in conjunction with nuclear magnetic resonance (NMR) and cross-linking mass spectrometry (XLMS) measurements are used to explore the interactions of αS with an anionic lipid bilayer. The simulations and NMR measurements together reveal a break in the helical structure of the central non-amyloid-β component (NAC) region of αS in the vicinity of residues 65-70, which may facilitate subsequent oligomer formation. Coarse-grained simulations of αS starting from the structure of αS when bound to a detergent micelle reveal the overall pattern of protein contacts to anionic lipid bilayers, while subsequent all-atom simulations provide details of conformational changes upon membrane binding. In particular, simulations and NMR data for liposome-bound αS indicate incipient β-strand formation in the NAC region, which is supported by intramolecular contacts seen XLMS and simulations. Markov state models based on the all-atom simulations suggest a mechanism of conformational change of membrane-bound αS a dynamic helix break in the region of residue 65 in the NAC region. The emergent dynamic model of membrane-interacting αS advances our understanding of the mechanism of PD, potentially aiding the design of novel therapeutic approaches.
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http://dx.doi.org/10.1021/acs.jpcb.1c01281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006134PMC
March 2021

Public Baseline and shared response structures support the theory of antibody repertoire functional commonality.

PLoS Comput Biol 2021 Mar 1;17(3):e1008781. Epub 2021 Mar 1.

Oxford Protein Informatics Group, Department of Statistics, University of Oxford, Oxford, United Kingdom.

The naïve antibody/B-cell receptor (BCR) repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger an effective antibody response to immunodominant epitopes. Sequence-based repertoire analysis has so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared ('public') antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we search for evidence of geometric similarity/convergence across human antibody repertoires. We first structurally profile naïve ('baseline') antibody diversity using snapshots from 41 unrelated individuals, predicting all modellable distinct structures within each repertoire. This analysis uncovers a high (much greater than random) degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' structures). Our approach is the first computational method to find levels of BCR commonality commensurate with epitope immunodominance and could therefore be harnessed to find more genetically distant antibodies with same-epitope complementarity. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes ('Public Response' structures). We show that Antibody Model Libraries derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening.
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http://dx.doi.org/10.1371/journal.pcbi.1008781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951972PMC
March 2021

Programming folding cooperativity of the dimeric i-motif with DNA frameworks for sensing small pH variations.

Chem Commun (Camb) 2021 Apr 1;57(26):3247-3250. Epub 2021 Mar 1.

Institute of Molecular Medicine, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

The response sensitivity of a molecular sensor is determined by the folding cooperativity of its responsive module. Using an H-responsive dimeric DNA i-motif as a model, we demonstrate the enhancement of its folding cooperativity through preorganization by a DNA framework, and with it we fabricate robust intracellular pH sensors with high response sensitivity.
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http://dx.doi.org/10.1039/d1cc00266jDOI Listing
April 2021

Ab-Ligity: identifying sequence-dissimilar antibodies that bind to the same epitope.

MAbs 2021 Jan-Dec;13(1):1873478

Department of Statistics, University of Oxford , Oxford, UK.

Solving the structure of an antibody-antigen complex gives atomic level information of the interactions between an antibody and its antigen, but such structures are expensive and hard to obtain. Alternative experimental sources include epitope mapping and binning experiments, which can be used as a surrogate to identify key interacting residues. However, their resolution is usually not sufficient to identify if two antibodies have identical interactions. Computational approaches to this problem have so far been based on the premise that antibodies with similar sequences behave similarly. Such approaches will fail to identify sequence-distant antibodies that target the same epitope. Here, we present Ab-Ligity, a structure-based similarity measure tailored to antibody-antigen interfaces. Using predicted paratopes on model antibody structures, we assessed its ability to identify those antibodies that target highly similar epitopes. Most antibodies adopting similar binding modes can be identified from sequence similarity alone, using methods such as clonotyping. In the challenging subset of antibodies whose sequences differ significantly, Ab-Ligity is still able to predict antibodies that would bind to highly similar epitopes (precision of 0.95 and recall of 0.69). We compared Ab-Ligity's performance to an existing tool for comparing general protein interfaces, InterComp, and showed improved performance on antibody cases achieved in a substantially reduced time. These results suggest that Ab-Ligity will allow the identification of diverse (sequence-dissimilar) antibodies that bind to the same epitopes from large datasets such as immune repertoires. The tool is available at http://opig.stats.ox.ac.uk/resources.
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http://dx.doi.org/10.1080/19420862.2021.1873478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833755PMC
January 2021

Probing Transient DNA Conformation Changes with an Intercalative Fluorescent Excimer.

Angew Chem Int Ed Engl 2021 03 3;60(12):6624-6630. Epub 2021 Feb 3.

Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800, China.

Variation of DNA conformation is important in regulating gene expression and mediating drug-DNA interactions. However, directly probing transient DNA conformation changes is challenging owing to the dynamic nature of this process. We show a label-free fluorescence method to monitor transient DNA conformation changes in DNA structures with various lengths and shapes using a DNA intercalator, K21. K21 can form transient excimers on the surface of DNA; the ratiometric emission of monomer and excimer correlate to DNA transient conformation stability in numerous DNA structures, including i-motifs, G-quadruplex structures, and single nucleotide mutation at random position. We analyzed the conformation dynamics of a single plasmid before and after enzyme digestion with confocal fluorescence microscopy. This method provides a label-free fluorescence strategy to probe transient conformation changes of DNA structures and has potential in uncovering transient genomic processes in living cells.
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http://dx.doi.org/10.1002/anie.202014466DOI Listing
March 2021

Computational study of the substituent effect of halogenated fused-ring heteroaromatics on halogen bonding.

J Mol Model 2020 Sep 15;26(10):270. Epub 2020 Sep 15.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Halogen bonding (XB) has been applied in many fields from crystal engineering to medicinal chemistry. Compared with the well-studied XB of simple halogenated aromatics, little research has been done on the XB of halogenated fused-ring heteroaromatics, a prevalent substructure in organic compounds. With 1H-pyrrolo[3,2-b]pyridines (PPs) as examples of novel fused-ring heteroaromatics with hydrogen bond donor and acceptor and XB donor, the XB formed by the halogenated heteroaromatics was explored in this study. With 4 different substituents, viz., -CH, -NH, -F, and -CONH, at different positions, 339 derivatives of brominated PP (Br-PP) were designed for calculating their electrostatic potential of the σ-hole of the halogen atom (V) and binding energy with ammonia as XB acceptor (E) at M06-2X/6-311++G(d,p) level by PCM model in dichloromethane. The calculated V values ranging from -1.3 to 35.1 kcal/mol and the calculated E ranging from -0.82 to -2.37 kcal/mol demonstrated that the XB is complicated and highly tunable. Noticeably, the electron-withdrawing substituents, especially at ortho-position, do not always increase the values of V, while the electron-donating substituents do not always decrease V. Similar results were observed from the calculation on 339 iodinated PPs at M06-2X/6-311++G(d,p) level. The complexity of the XB formed by the halogenated fused ring heteroaromatics indicated a great potential of tuning its strength by different substituents at different positions and revealed a necessity of quantum chemistry calculation for predicting the XB.Graphical abstract.
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http://dx.doi.org/10.1007/s00894-020-04534-xDOI Listing
September 2020

DNA Framework-Supported Electrochemical Analysis of DNA Methylation for Prostate Cancers.

Nano Lett 2020 10 10;20(10):7028-7035. Epub 2020 Sep 10.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China.

Epigenetic alterations hold great promise as biomarkers for early stage cancer diagnosis. Nevertheless, direct identification of rare methylated DNA in the genome remains challenging. Here, we report an ultrasensitive framework nucleic acid-based electrochemical sensor for quantitative and highly selective analysis of DNA methylation. Notably, we can detect 160 fg of methylated DNA in million-fold unmethylated DNA samples using this electrochemical methylation-specific polymerase chain reaction (E-MSP) method. The high sensitivity of E-MSP enables one-step detection of low-abundance methylation at two different genes in patient serum samples. By using a combination test with two methylation alterations, we achieve high accuracy and sensitivity for reliable differentiation of prostate cancer and benign prostate hypertrophy (BPH). This new method sheds new light on translational use in early cancer diagnosis and in monitoring patients' responses to therapeutic agents.
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http://dx.doi.org/10.1021/acs.nanolett.0c01898DOI Listing
October 2020

Programmable Live-Cell CRISPR Imaging with Toehold-Switch-Mediated Strand Displacement.

Angew Chem Int Ed Engl 2020 11 7;59(46):20612-20618. Epub 2020 Sep 7.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.

The widespread application of CRISPR-Cas9 has transformed genome engineering. Nevertheless, the precision to control the targeting activity of Cas9 requires further improvement. We report a toehold-switch-based approach to engineer the conformation of single guide RNA (sgRNA) for programmable activation of Cas9. This activation circuit is responsive to multiple inputs and can regulate the conformation of the sgRNA through toehold-switch-mediated strand displacement. We demonstrate the orthogonal suppression and activation of Cas9 with orthogonal DNA inputs. Combination of toehold switches leads to a variety of intracellular Cas9 activation programs with simultaneous and orthogonal responses, through which multiple genome loci are displayed in different colors in a controllable manner. This approach provides a new route for programing CRISPR in living cells for genome imaging and engineering.
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http://dx.doi.org/10.1002/anie.202009062DOI Listing
November 2020

Encapsulation and release of living tumor cells using hydrogels with the hybridization chain reaction.

Nat Protoc 2020 07 22;15(7):2163-2185. Epub 2020 Jun 22.

Institute of Molecular Medicine, Department of Laboratory Medicine, Shanghai Key Laboratory for Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, School of Medicine and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China.

Circulating tumor cells (CTCs) enable noninvasive liquid biopsy and identification of cancer. Various approaches exist for the capture and release of CTCs, including microfluidic methods and those involving magnetic beads or nanostructured solid interfaces. However, the concomitant cell damage and fragmentation that often occur during capture make it difficult to extensively characterize and analyze living CTCs. Here, we describe an aptamer-trigger-clamped hybridization chain reaction (atcHCR) method for the capture of CTCs by porous 3D DNA hydrogels. The 3D environment of the DNA networks minimizes cell damage, and the CTCs can subsequently be released for live-cell analysis. In this protocol, initiator DNAs with aptamer-toehold biblocks specifically bind to the epithelial cell adhesion molecule (EpCAM) on the surface of CTCs, which triggers the atcHCR and the formation of a DNA hydrogel. The DNA hydrogel cloaks the CTCs, facilitating quantification with minimal cell damage. This method can be used to quantitively identify as few as 10 MCF-7 cells in a 2-µL blood sample. Decloaking of tumor cells via gentle chemical stimulus (ATP) is used to release living tumor cells for subsequent cell culture and live-cell analysis. We also describe how to use the protocol to encapsulate and release cells of cancer cell lines, which can be used in preliminary experiments to model CTCs. The whole protocol takes ~2.5 d to complete, including downstream cell culture and analysis.
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http://dx.doi.org/10.1038/s41596-020-0326-4DOI Listing
July 2020

Programming Switchable Transcription of Topologically Constrained DNA.

J Am Chem Soc 2020 06 5;142(24):10739-10746. Epub 2020 Jun 5.

School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, Shanghai 200240, China.

Genomic DNA is compacted via chromatin condensation in mammalian cells, and transcription of such topologically constrained DNA to messenger RNA is under strict spatiotemporal regulation. Nevertheless, control of DNA topology has been poorly explored in transcription and gene transfection. Here we report the construction of topologically ordered (TO-) prokaryotic genes composed of linear DNA templates appended with a T7 promoter sequence with the use of DNA self-assembly. We find that TO-DNA maintains the transcription activity whereas the activity is critically dependent on the configuration of the T7 promoter in a folded DNA nanostructure. By prescribing the position and the intactness of the T7 promoter, we can dynamically activate or repress transcription in response to specific DNA key strands in a Boolean logic manner. Bioorthogonal switchable transcription is realized with the insertion of multiple genes in a TO-DNA. Further, implementing TO-DNA in living bacteria leads to switchable transcription of fluorescent RNA aptamers for light-up cell imaging. Hence, the design of TO-DNAs provides a means for shape-dependent gene delivery, enriching the toolbox of genetic engineering and synthetic biology.
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http://dx.doi.org/10.1021/jacs.0c01962DOI Listing
June 2020

DNA Origami-Enabled Engineering of Ligand-Drug Conjugates for Targeted Drug Delivery.

Small 2020 04 19;16(16):e1904857. Epub 2020 Mar 19.

School of Chemistry and Chemical Engineering and Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.

Effective drug delivery systems that can systematically and selectively transport payloads to disease cells remain a challenge. Here, a targeting ligand-modified DNA origami nanostructure (DON) as an antibody-drug conjugate (ADC)-like carrier for targeted prostate cancer therapy is reported. Specifically, DON of six helical bundles is modified with a ligand 2-[3-(1,3-dicarboxy propyl)-ureido] pentanedioic acid (DUPA) against prostate-specific membrane antigen (PSMA), to serve as the antibody for drug conjugation in ADC. Doxorubicin (Dox) is then loaded to DON through intercalation to dsDNA. This platform features in spatially controllable organization of targeting ligands and high drug loading capacity. With this nanocomposite, selective delivery of Dox to the PSMA+ cancer cell line LNCaP is readily achieved. The consequent therapeutic efficacy is critically dependent on the numbers of targeting ligand assembled on DON. This target-specific and biocompatible drug delivery platform with high maximum tolerated doses shows immense potential for developing novel nanomedicine.
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http://dx.doi.org/10.1002/smll.201904857DOI Listing
April 2020

TCRBuilder: multi-state T-cell receptor structure prediction.

Bioinformatics 2020 06;36(11):3580-3581

Department of Statistics, University of Oxford, Oxford OX1 3LB, UK.

Motivation: T-cell receptors (TCRs) are immune proteins that primarily target peptide antigens presented by the major histocompatibility complex. They tend to have lower specificity and affinity than their antibody counterparts, and their binding sites have been shown to adopt multiple conformations, which is potentially an important factor for their polyspecificity. None of the current TCR-modelling tools predict this variability which limits our ability to accurately predict TCR binding.

Results: We present TCRBuilder, a multi-state TCR structure prediction tool. Given a paired αβTCR sequence, TCRBuilder returns a model or an ensemble of models covering the potential conformations of the binding site. This enables the analysis of structurally driven polyspecificity in TCRs, which is not possible with existing tools.

Availability And Implementation: http://opig.stats.ox.ac.uk/resources.

Contact: [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa194DOI Listing
June 2020

Programming bulk enzyme heterojunctions for biosensor development with tetrahedral DNA framework.

Nat Commun 2020 02 11;11(1):838. Epub 2020 Feb 11.

Institute of Molecular Medicine, Department of Urology, Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.

Protein-protein interactions are spatially regulated in living cells to realize high reaction efficiency, as seen in naturally existing electron-transfer chains. Nevertheless, arrangement of chemical/biochemical components at the artificial device interfaces does not possess the same level of control. Here we report a tetrahedral DNA framework-enabled bulk enzyme heterojunction (BEH) strategy to program the multi-enzyme catalytic cascade at the interface of electrochemical biosensors. The construction of interpenetrating network of BEH at the millimeter-scale electrode interface brings enzyme pairs within the critical coupling length (CCL) of ~10 nm, which in turn greatly improve the overall catalytic cascade efficiency by ~10-fold. We demonstrate the BEH generality with a range of enzyme pairs for electrochemically detecting clinically relevant molecular targets. As a proof of concept, a BEH-based sarcosine sensor enables single-step detection of the metabolic biomarker of sarcosine with ultrasensitivity, which hold the potential for precision diagnosis of early-stage prostate cancer.
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http://dx.doi.org/10.1038/s41467-020-14664-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012893PMC
February 2020

Exploring Conformational Change of Adenylate Kinase by Replica Exchange Molecular Dynamic Simulation.

Biophys J 2020 03 9;118(5):1009-1018. Epub 2020 Jan 9.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Open Studio for Druggability Research of Marine Lead Compounds, Qingdao National Laboratory for Marine Science and Technology, Jimo, Qingdao, China; University of Chinese Academy of Sciences, Beijing, China. Electronic address:

Replica exchange molecular dynamics (REMD) simulation is a popular enhanced sampling method that is widely used for exploring the atomic mechanism of protein conformational change. However, the requirement of huge computational resources for REMD, especially with the explicit solvent model, largely limits its application. In this study, the availability and efficiency of a variant of velocity-scaling REMD (vsREMD) was assessed with adenylate kinase as an example. Although vsREMD achieved results consistent with those from conventional REMD and experimental studies, the number of replicas required for vsREMD (30) was much less than that for conventional REMD (80) to achieve a similar acceptance rate (∼0.2), demonstrating high efficiency of vsREMD to characterize the protein conformational change and associated free-energy profile. Thus, vsREMD is a highly efficient approach for studying the large-scale conformational change of protein systems.
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http://dx.doi.org/10.1016/j.bpj.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063423PMC
March 2020

Implementing digital computing with DNA-based switching circuits.

Nat Commun 2020 01 8;11(1):121. Epub 2020 Jan 8.

School of Chemistry and Chemical Engineering, Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 201240, China.

DNA strand displacement reactions (SDRs) provide a set of intelligent toolboxes for developing molecular computation. Whereas SDR-based logic gate circuits have achieved a high level of complexity, the scale-up for practical achievable computational tasks remains a hurdle. Switching circuits that were originally proposed by Shannon in 1938 and nowadays widely used in telecommunication represent an alternative and efficient means to realize fast-speed and high-bandwidth communication. Here we develop SDR-based DNA switching circuits (DSCs) for implementing digital computing. Using a routing strategy on a programmable DNA switch canvas, we show that arbitrary Boolean functions can be represented by DSCs and implemented with molecular switches with high computing speed. We further demonstrate the implementation of full-adder and square-rooting functions using DSCs, which only uses down to 1/4 DNA strands as compared with a dual-rail logic expression-based design. We expect that DSCs provide a design paradigm for digital computation with biomolecules.
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http://dx.doi.org/10.1038/s41467-019-13980-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949259PMC
January 2020

Conformation of the Macrocyclic Drug Lorlatinib in Polar and Nonpolar Environments: A MD Simulation and NMR Study.

ACS Omega 2019 Dec 16;4(26):22245-22250. Epub 2019 Dec 16.

Department of Chemistry-BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.

The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of the macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical to its target bound structure. This conformer is stabilized by an extensive hydrogen bond network to the solvents. In chloroform, lorlatinib populates two conformers with the second one being less polar, which may contribute to lorlatinib's ability to cross cell membranes.
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http://dx.doi.org/10.1021/acsomega.9b03797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933765PMC
December 2019

Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2.

Structure 2020 02 2;28(2):169-184.e5. Epub 2019 Dec 2.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

Polycystin-2 (PC2) is a transient receptor potential (TRP) channel present in ciliary membranes of the kidney. PC2 shares a transmembrane fold with other TRP channels, in addition to an extracellular domain found in TRPP and TRPML channels. Using molecular dynamics (MD) simulations and cryoelectron microscopy we identify and characterize PIP and cholesterol interactions with PC2. PC2 is revealed to have a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel. A 3.0-Å structure reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are characterized by MD simulations. The two classes of lipid binding sites are compared with sites observed in other TRPs and in Kv channels. These findings suggest PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol, and position PC2 within an emerging model of the roles of lipids in the regulation and organization of ciliary membranes.
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http://dx.doi.org/10.1016/j.str.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001106PMC
February 2020

DNA origami cryptography for secure communication.

Nat Commun 2019 11 29;10(1):5469. Epub 2019 Nov 29.

School of Chemistry and Chemical Engineering, and Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.

Biomolecular cryptography exploiting specific biomolecular interactions for data encryption represents a unique approach for information security. However, constructing protocols based on biomolecular reactions to guarantee confidentiality, integrity and availability (CIA) of information remains a challenge. Here we develop DNA origami cryptography (DOC) that exploits folding of a M13 viral scaffold into nanometer-scale self-assembled braille-like patterns for secure communication, which can create a key with a size of over 700 bits. The intrinsic nanoscale addressability of DNA origami additionally allows for protein binding-based steganography, which further protects message confidentiality in DOC. The integrity of a transmitted message can be ensured by establishing specific linkages between several DNA origamis carrying parts of the message. The versatility of DOC is further demonstrated by transmitting various data formats including text, musical notes and images, supporting its great potential for meeting the rapidly increasing CIA demands of next-generation cryptography.
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http://dx.doi.org/10.1038/s41467-019-13517-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884444PMC
November 2019

Thera-SAbDab: the Therapeutic Structural Antibody Database.

Nucleic Acids Res 2020 01;48(D1):D383-D388

Oxford Protein Informatics Group, Department of Statistics, University of Oxford, 24-29 St Giles', Oxford OX1 3LB, UK.

The Therapeutic Structural Antibody Database (Thera-SAbDab; http://opig.stats.ox.ac.uk/webapps/therasabdab) tracks all antibody- and nanobody-related therapeutics recognized by the World Health Organisation (WHO), and identifies any corresponding structures in the Structural Antibody Database (SAbDab) with near-exact or exact variable domain sequence matches. Thera-SAbDab is synchronized with SAbDab to update weekly, reflecting new Protein Data Bank entries and the availability of new sequence data published by the WHO. Each therapeutic summary page lists structural coverage (with links to the appropriate SAbDab entries), alignments showing where any near-matches deviate in sequence, and accompanying metadata, such as intended target and investigated conditions. Thera-SAbDab can be queried by therapeutic name, by a combination of metadata, or by variable domain sequence - returning all therapeutics that are within a specified sequence identity over a specified region of the query. The sequences of all therapeutics listed in Thera-SAbDab (461 unique molecules, as of 5 August 2019) are downloadable as a single file with accompanying metadata.
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http://dx.doi.org/10.1093/nar/gkz827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943036PMC
January 2020

B-cell epitopes: Discontinuity and conformational analysis.

Mol Immunol 2019 10 20;114:643-650. Epub 2019 Sep 20.

Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK. Electronic address:

Peptide vaccines have many potential advantages over conventional ones including low cost, lack of need for cold-chain storage, safety and specificity. However, it is well known that approximately 90% of B-cell epitopes (BCEs) are discontinuous in nature making it difficult to mimic them for creating vaccines. In this study, the degree of discontinuity in B-cell epitopes and their conformational nature is examined. The discontinuity of B-cell epitopes is analyzed by defining 'regions' (consisting of at least three antibody-contacting residues each separated by ≤3 residues) and small fragments (antibody-contacting residues that do not satisfy the requirements for a region). Secondly, an algorithm has been developed that classifies each region's shape as straight, curved or folded on the basis that straight and folded regions are more likely to retain their native conformation as isolated peptides. We have investigated the structures of 488 B-cell epitopes from which 1282 regions and 1018 fragments have been identified. 90% of epitopes have five or fewer regions and five or fewer fragments with 14% containing only one region and 4% being truly linear (i.e. having one region and no fragments). Of the 1282 regions, 508 are straight in shape, 626 are curved and 148 are folded.
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http://dx.doi.org/10.1016/j.molimm.2019.09.014DOI Listing
October 2019

Underestimated Noncovalent Interactions in Protein Data Bank.

J Chem Inf Model 2019 08 25;59(8):3389-3399. Epub 2019 Jul 25.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.

Noncovalent interactions (NCIs) play essential roles in the structure and function of biomacromolecules. There are various NCIs, e.g., hydrogen bonds (HBs), cation-π and π-π interactions, and ionic bonds, among which HBs are the most widespread and well-studied. By utilizing the ratio of the observed HBs over pseudo HBs (1.0 Å longer than the HB distance criteria without angle constraints), we demonstrated that HBs in both protein-ligand and protein-protein interfaces are overlooked in structures deposited in PDB. After the QM/MM optimization of 12 protein-ligand complexes, we showed that the overlooked HBs could be recovered. With a systematic search in the PDB, we found that the HB number per residue () in proteins decreases as structural resolution becomes lower, implying that HBs are overlooked even today, regardless of the type of refinement approach used. Similarly, cation-π, π-π, and ionic interactions were found to be significantly lost, manifesting the universal underestimation of various NCIs. Considering the vital role of NCIs, it is important to recover the NCIs to facilitate drug design, to explore protein-protein interaction, and to study protein structure and function.
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http://dx.doi.org/10.1021/acs.jcim.9b00258DOI Listing
August 2019

Fractal Nanoplasmonic Labels for Supermultiplex Imaging in Single Cells.

J Am Chem Soc 2019 07 18;141(30):11938-11946. Epub 2019 Jul 18.

School of Chemistry and Chemical Engineering, and Institute of Molecular Medicine, Renji Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai 200240 , China.

The rapidly increasing need for systems biology stimulates the development of supermultiplex (SM) methods for simultaneously labeling multiple biomolecules/cells with distinct colors. Here we report the development of DNA-engineered fractal nanoplasmonic labels with ultrahigh brightness and photostability for SM imaging in single cells. These color-resolvable nanoplasmonic labels have a uniform size of ∼50 nm with an inner hollow gap of ∼1 nm. The outer shell morphology is highly tunable with the tip aspect ratio covering the range of δ = 0.29-1.66, which supports SM plasmonic imaging exceeding the conventional fluorescence multiplexing limit. We demonstrate the use of these SM labels for quantitative imaging of receptor-mediated endocytosis and intracellular transport of multiple protein-NP structures in a single cell in real time. This SM-plasmonic method sheds light on elucidating complex interactions among protein-NPs in nanotoxicology and facilitates the development of novel nanomedicines for diagnosis and therapy.
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http://dx.doi.org/10.1021/jacs.9b03498DOI Listing
July 2019

D3Pockets: A Method and Web Server for Systematic Analysis of Protein Pocket Dynamics.

J Chem Inf Model 2019 08 16;59(8):3353-3358. Epub 2019 Jul 16.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203 , China.

The intrinsic dynamic properties of the ligand-binding pockets of proteins are important for the protein function mechanism and thus are useful to drug discovery and development. Few methods are available to study the dynamic properties, such as pocket stability, continuity, and correlation. In this work, we develop a method and web server, namely, D3Pockets, for exploring the dynamic properties of the protein pocket based on either molecular dynamics (MD) simulation trajectories or conformational ensembles. Application of D3Pockets on five target proteins as examples, namely, HIV-1 protease, BACE1, L-ABP, GPX4, and GR, uncovers more information on the dynamic properties of the ligand-binding pockets, which should be helpful to understanding protein function mechanism and drug design. The D3Pockets web server is available at http://www.d3pharma.com/D3Pocket/index.php .
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http://dx.doi.org/10.1021/acs.jcim.9b00332DOI Listing
August 2019

Halogen bonding in differently charged complexes: basic profile, essential interaction terms and intrinsic σ-hole.

Phys Chem Chem Phys 2019 Jul;21(27):15106-15119

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. and University of Chinese Academy of Sciences, Beijing 100049, China and Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, China.

Studies on halogen bonds (XB) between organohalogens and their acceptors in crystal structures revealed that the XB donor and acceptor could be differently charged, making it difficult to understand the nature of the interaction, especially the negatively charged donor's electrophilicity and positively charged acceptor's nucleophilicity. In this paper, 9 XB systems mimicking all possibly charged halogen bonding interactions were designed and explored computationally. The results revealed that all XBs could be stable, with binding energies after removing background interaction as strong as -1.2, -3.4, and -8.3 kcal mol-1 for Cl, Br, and I involved XBs respectively. Orbital and dispersion interactions are found to be always attractive while unidirectional intermolecular electron transfer from a XB acceptor to a XB donor occurs in all XB complexes. These observations could be attributed to the intrinsic σ-hole of the XB donor and the intrinsic electronic properties of the XB acceptor regardless of their charge states. Intramolecular charge redistribution inside both the donor and the acceptor is found to be system-dependent but always leads to a more stable XB. Accordingly, this study demonstrates that the orbital-based origin of halogen bonds could successfully interpret the complicated behaviour of differently charged XB complexes, while electrostatic interaction may dramatically change the overall bonding strength. The results should further promote the application of halogens in all related areas.
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http://dx.doi.org/10.1039/c9cp01379bDOI Listing
July 2019