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Exploring the Mutational Robustness of Nucleic Acids by Searching Genotype Neighborhoods in Sequence Space

JOURNAL OF PHYSICAL CHEMISTRY LETTERS 2017年第2期8卷 407-414页

作者： Zhou, Qingtong Sun, Xianbao Xia, Xiaole Fan, Zhou Luo, zhaofeng zhao, suwen Shakhnovich, Eugene Liang, Haojun ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China Univ Sci & Technol China Collaborat Innovat Ctr Chem Energy Mat Hefei Natl Lab Phys Sci Microscale CAS Key Lab Soft Matter ChemDept Polymer Sci & E Hefei 230026 Anhui Peoples R China Jiangnan Univ Sch Biotechnol Key Lab Ind Biotechnol Minist Educ Wuxi 214122 Jiangsu Peoples R China Chinese Acad Sci CAS MPG Partner Inst Computat Biol Max Planck Independent Res Grp Populat Genom Key Lab Computat BiolShanghai Inst Biol Sci Shanghai 200031 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Sci & Technol China Sch Life Sci Hefei 230026 Anhui Peoples R China Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA

To assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed, where nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanisms through which mutations alter the structural, dynamic, and functional properties of nucleic acids are poorly understood. Here we performed a SELEX in silico study to investigate the fitness distribution of the L-Arm-binding aptamer genotype neighborhoods. Two novel functional genotype neighborhoods were isolated and experimentally verified to have comparable fitness as the wild-type. The experimental aptamer fitness landscape suggests the mutational robustness is strongly influenced by the local base environment and ligand-binding mode, whereas bases distant from the binding pocket provide potential evolutionary pathways to approach the global fitness maximum. Our work provides an example of successful application of SELEX in silico to optimize an aptamer and demonstrates the strong sensitivity of mutational robustness to the site of genetic variation.

关键词： Free energy Nucleic acids Peptides and proteins Ligands Genetics

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Predicting Enzyme-Substrate Specificity with QM/MM Methods: A Case Study of the Stereospecificity of D-Glucarate Dehydratase

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BIOCHEMISTRY 2013年第33期52卷 5511-5513页

作者： Tian, Boxue Wallrapp, Frank Kalyanaraman, Chakrapani zhao, suwen Eriksson, Leif A. Jacobson, Matthew P. Natl Univ Ireland Sch Chem Galway Ireland Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94158 USA Univ Gothenburg Dept Chem & Mol Biol S-41296 Gothenburg Sweden

The stereospecificity of D-glucarate dehydratase (GlucD) is explored by QM/MM calculations. Both the substrate binding and the chemical steps of GlucD contribute to substrate specificity. Although the identification of transition states remains computationally intensive, we suggest that QM/MM computations on ground states or intermediates can capture aspects of specificity that cannot be obtained using docking or molecular mechanics methods.

关键词： STEREOSPECIFICITY ENZYMES MOLECULES QUANTUM mechanics QUANTUM theory MATRIX mechanics

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Crystal structure of a constitutive active mutant of adenosine A2A receptor

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IUCRJ 2022年第Pt 3期9卷 333-341页

作者： Cui, Min Zhou, Qingtong Xu, Yueming Weng, Yuan Yao, Deqiang zhao, suwen Song, Gaojie East China Normal Univ Inst Biomed Sci Shanghai Key Lab Regulatory Biol Shanghai 200241 Peoples R China East China Normal Univ Sch Life Sci Shanghai 200241 Peoples R China Fudan Univ Sch Basic Med Sci Dept Pharmacol Shanghai 200032 Peoples R China Shanghai Jiao Tong Univ Ren Ji Hosp Sch Med State Key Lab Oncogenes & Related Genes Shanghai 200127 Peoples R China ShanghaiTech Univ iHuman Inst Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China

The adenosine A(2A) receptor (A(2A)AR) is a prototypical member of the class A subfamily of G-protein-coupled receptors (GPCRs) that is widely distributed in various tissues and organs of the human body, and participates in many important signal-regulation processes. We have previously summarized a common activation pathway of class A GPCRs in which a series of conserved residues/motifs undergo conformational change during extracellular agonist binding and finally induce the coupling of intracellular G protein. Through this mechanism we have successfully predicted several novel constitutive active or inactive mutations for A(2A)AR. To reveal the molecular mechanism of mutation-induced constitutive activity, we determined the structure of a typical mutant I92N complexed with the agonist UK-432097. The mutated I92N forms a hydrophilic interaction network with nearby residues including Trp(6.48) of the CWxP motif, which is absent in wild-type A(2A)AR. Although the mutant structure is similar overall to the previously determined intermediate-state A(2A)AR structure (PDB ID 3qak) [Xu, Wu, Katritch, Han, Jacobson, Gao, Cherezov & Stevens (2011). Science, 332, 322-327], molecular dynamics simulations suggest that the I92N mutant stabilizes the metastable intermediate state through the hydrophilic interaction network and favors the conformational transition of the receptor towards the active state. This research provides a structural template towards the special pharmacological outcome triggered by conformational mutation and sheds light on future structural or pharmacological studies among class A GPCRs.

关键词： constitutive active mutants adenosine A(2A) receptors crystal structures hydrophilic interaction networks molecular dynamics G-protein-coupled receptors agonists

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Structural and biofunctional evaluation of decellularized jellyfish matrices

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JOURNAL OF MATERIALS CHEMISTRY B 2023年第16期11卷 3740-3751页

作者： zhao, Jie Yu, Wenjun Zhang, Qi Li, Xiaojing Huang, Yongjie zhao, suwen Li, Tao Liu, Shanshan Li, Yang Shan, Hong Sun Yat Sen Univ Affiliated Hosp 5 Guangdong Prov Engn Res Ctr Mol Imaging Zhuhai 519000 Peoples R China Sun Yat Sen Univ Affiliated Hosp 5 Dept Radiol Zhuhai 519000 Peoples R China Sun Yat Sen Univ Affiliated Hosp 5 Cardiovasc Ctr Cardiac Surg & Struct Heart Dis Unit Zhuhai 519000 Peoples R China Sun Yat Sen Univ Affiliated Hosp 5 Dept Crit Care Med Surg Intens Care Unit Zhuhai 519000 Peoples R China Sun Yat Sen Univ Affiliated Hosp 5 Dept Intervent Med Zhuhai 519000 Peoples R China

Extracellular matrices decellularized from marine animal tissues are emerging scaffolds in tissue engineering. Jellyfish tissues are suitable for making functional and safe decellularized matrices in part due to their simple structure, high water content, and low risk of pathogen transmission to humans. Jellyfish are some of the most prevalent marine animals, but their decellularized matrices have remained largely undeveloped. Here we evaluated the structures and functions of the jellyfish (Rhopilema esculentum) matrices decellularized with seven different detergents. All of them showed effectiveness in removing the cellular components. Scanning electron microscopy and mechanical testing revealed that the decellularized matrices mostly retained the native microstructures, whereas only SDS and SNL distorted the matrices' multilayered and fibrous architecture. The collagen hybridizing peptide fluorescence staining showed that SDS, SNL, Triton X-100, IGEPAL, and Tween-20 denatured the jellyfish collagen molecules to varying degrees while CHAPS and SD protected the collagen's triple-helix conformation. We demonstrated that the decellularized jellyfish matrices showed similarity to different types of mammalian collagen and supported the adhesion and proliferation of human dermal and corneal fibroblasts and mouse chondrocytes in 3D culture. Importantly, the decellularized jellyfish matrix also facilitated wound healing in vivo by reducing inflammation while promoting angiogenesis and tissue remodeling. Taken together, our study demonstrated that the decellularized jellyfish matrices are an easy-to-prepare, biocompatible, and potentially widely applicable scaffold for regenerative medicine.

关键词： Collagen

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Purification, characterization, and application of a high activity 3-ketosteroid-Δ¹-dehydrogenase from Mycobacterium neoaurum DSM 1381

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APPLIED MICROBIOLOGY AND BIOTECHNOLOGY 2019年第16期103卷 6605-6616页

作者： Zhang, Ruijie Xu, Xuexia Cao, Huijin Yuan, Chenyang Yuminaga, Yuki zhao, suwen Shi, Jiping Zhang, Baoguo Chinese Acad Sci Shanghai Adv Res Inst Lab Biorefinery 99 Haike Rd Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol Shanghai 201210 Peoples R China Univ Chinese Acad Sci Beijing 100049 Peoples R China ShanghaiTech Univ IHuman Inst Shanghai 201210 Peoples R China

Delta(1)-Dehydrogenation is one of the most important reactions for steroid drug modification. Numerous 3-ketosteroid-Delta(1)-dehydrogenases (KstDs) catalyzing this reaction were observed in various organisms. However, only a few have been characterized and used for substrate conversion. In this study, a promising enzyme (KstD2) from Mycobacterium neoaurum DSM 1381 was purified and characterized. Interestingly, KstD2 displayed a high activity on a range of substrates, including 17 alpha-hydroxypregn-4-ene-3,20-dione (17 alpha-OH-P);androsta-4,9(11)-diene-3,17-dione (NSC 44826);and 4-androstene-3,17-dione (AD). These reactions were performed under optimal conditions at 40 degrees C and pH 8.0. Noteworthy, both the activity and stability of the enzyme were sensitive to various metal ions. After optimizing the expression and biocatalyst conditions, up to 1586 U mg(-1) intracellular KstD activity on AD could be produced. Furthermore, the associated conversion rate was 99% with 30 g L-1 AD after 8 h. On the other hand, we obtained 99%, 90%, and over 80% of conversion with 20 g L-1 NSC 44826;10 g L-1 16,17 alpha-epoxyprogesterone;and 20 g L-1 17 alpha-OH-P or canrenone, respectively, after 24 h. Sequence homology and structural analyses indicated that the residue R178 located in a unique short loop among cluster 2 is crucial for substrate recognition which was confirmed by mutagenesis. In summary, this study reports on the first purification and characterization of a KstD from cluster 2. Its remarkable properties deserve more attention to potentially lead to further industrial applications.

关键词： 3-Ketosteroid-Delta(1)-dehydrogenase Mycobacterium neoaurum Biocatalysis Steroids Heterogeneous expression

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Therapeutic hypertension system based on a microbreathing pressure sensor system

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MEDICAL DEVICES-EVIDENCE AND RESEARCH 2011年第1期4卷 51-57页

作者： Diao, Ziji Liu, Hongying Zhu, Lan Gao, Xiaoqiang zhao, suwen Pi, Xitian Zheng, Xiaolin Chongqing Univ Key Lab Biorheol Sci & Technol Minist Educ Chongqing Peoples R China Key Labs Natl Def Sci & Technol Innovat Micronano Chongqing Peoples R China

Background and methods: A novel therapeutic system for the treatment of hypertension was developed on the basis of a slow-breath training mechanism, using a microbreathing pressure sensor device for the detection of human respiratory signals attached to the abdomen. The system utilizes a single-chip AT89C51 microcomputer as a core processor, programmed by Microsoft Visual C++6.0 to communicate with a PC via a full-speed PDIUSBD12 interface chip. The programming is based on a slow-breath guided algorithm in which the respiratory signal serves as a physiological feedback parameter. Inhalation and exhalation by the subject is guided by music signals. Results and conclusion: Our study indicates that this microbreathing sensor system may assist in slow-breath training and may help to decrease blood pressure.

关键词： hypertension microbreathing sensor single-chip microcomputer slow-pace breathing

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Structural insights into the committed step of bacterial phospholipid biosynthesis

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NATURE COMMUNICATIONS 2017年第1期8卷 1691页

作者： Li, Zhenjian Tang, Yannan Wu, Yiran zhao, suwen Bao, Juan Luo, Yitian Li, Dianfan Chinese Acad Sci Shanghai Inst Biochem & Cell Biol Ctr Excellence Mol Cell Sci Natl Ctr Prot Sci ShanghaiState Key Lab Mol Biol 333 Haike Rd Shanghai 201210 Peoples R China Univ Chinese Acad Sci Shanghai 201210 Peoples R China ShanghaiTech Univ iHuman Inst 333 Middle Huaxia Rd Shanghai 201210 Peoples R China ShanghaiTech Univ Sch Life Sci & Technol 333 Middle Huaxia Rd Shanghai 201210 Peoples R China

The membrane-integral glycerol 3-phosphate (G3P) acyltransferase PlsY catalyses the committed and essential step in bacterial phospholipid biosynthesis by acylation of G3P, forming lysophosphatidic acid. It contains no known acyltransferase motifs, lacks eukaryotic homologs, and uses the unusual acyl-phosphate as acyl donor, as opposed to acyl-CoA or acyl-carrier protein for other acyltransferases. Previous studies have identified several PlsY inhibitors as potential antimicrobials. Here we determine the crystal structure of PlsY at 1.48 angstrom resolution, revealing a seven-transmembrane helix fold. Four additional substrate-and product-bound structures uncover the atomic details of its relatively inflexible active site. Structure and mutagenesis suggest a different acylation mechanism of 'substrate-assisted catalysis' that, unlike other acyltransferases, does not require a proteinaceous catalytic base to complete. The structure data and a high-throughput enzymatic assay developed in this work should prove useful for virtual and experimental screening of inhibitors against this vital bacterial enzyme.

关键词： Nanocrystallography Phospholipids

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Localization of site-specific delivery capsule in vivo with alternating electromagnetic field

Localization of site-specific delivery capsule in vivo with ...

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World Automation Congress 2008

作者： Pi, Xitian zhao, suwen Liu, Hongying Xia, Bin Shi, Xiaoquan Zheng, Xiaolin Chongqing Univ Coll Bioengn Chongqing 400030 Peoples R China

ISBN: (纸本)9781889335384

Site-specific delivery capsule (SSDC) is a robotic capsule. It can load with drug and deliver the drug to the selected sites of human or animals' gut. In order to know whether the capsule have moved into the selected sites, we use receiving coils to detect the magnetic field generated by the eddy current in batteries of the capsule when the capsule exists in the alternating magnetic field. Experiment in simulative conditions of gastrointestinal (GI) tract is carried out and the result verifies the effectiveness of this method.

关键词： Electromagnetic fields

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Toward better refinement of comparative models: Predicting loops in inexact environments

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PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS 2008年第3期72卷 959-971页

作者： Sellers, Benjamin D. Zhu, Kai zhao, suwen Friesner, Richard A. Jacobson, Matthew P. Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94158 USA Univ Calif San Francisco Grad Grp Biophys San Francisco CA 94143 USA Columbia Univ Dept Chem New York NY 10027 USA

Achieving atomic-level accuracy in comparative protein models is limited by our ability to refine the initial, homolog-derived model closer to the native state. Despite considerable effort, progress in developing a generalized refinement method has been limited. In contrast, methods have been described that can accurately reconstruct loop conformations in native protein structures. We hypothesize that loop refinement in homology models is much more difficult than loop reconstruction in crystal structures, in part, because side-chain, backbone, and other structural inaccuracies surrounding the loop create a challenging sampling problem;the loop cannot be refined without simultaneously refining adjacent portions. In this work, we single out one sampling issue in an artificial but useful test set and examine how loop refinement accuracy is affected by errors in surrounding side-chains. In 80 high-resolution crystal structures, we first perturbed 6-12 residue loops away from the crystal conformation, and placed all protein side chains in non-native but low energy conformations. Even these relatively small perturbations in the surroundings made the loop prediction problem much more challenging. Using a previously published loop prediction method, median backbone (N-C alpha-C-O) RMSD's for groups of 6, 8, 10, and 12 residue loops are 0.3/0.6/0.4/0.6 angstrom, respectively, on native structures and increase to 1.1/2.2/1.5/2.3 angstrom on the perturbed cases. We then augmented our previous loop prediction method to simultaneously optimize the rotamer states of side chains surrounding the loop. Our results show that this augmented loop prediction method can recover the native state in many perturbed structures where the previous method failed, the median RMSD's for the 6, 8, 10, and 12 residue perturbed loops improve to 0.4/0.8/1.1/1.2 angstrom. Finally, we highlight three comparative models from blind tests, in which our new method predicted loops closer to the native confo

关键词： comparative homology modeling refinement loop prediction molecular mechanics force field

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Cryo-EM structure of Z-genome phage and ZTCG DNA

Cryo-EM structure of Z-genome phage and ZTCG DNA

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第二十次中国暨国际生物物理大会

作者： Jing Lin suwen zhao iHuman Institute ShanghaiTech University School of Life Science and Technology ShanghaiTech University

2-aminoadenine (Z) fully replaces adenine in the genomes of hundreds of bacteriophages. It is known that Z genome DNA (ZTCG DNA) has different physical, chemical and mechanical properties since Z pairs with T through three hydrogen bonds. However, the structural details behind the special properties of Z-genome phage and ZTCG DNA remain elusive. Here, we present cryo-EM structures of Z-genome phage SH-Ab 15497, including its capsid, portal, major tail protein and the ZTCG DNA located within the portal.

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