ChemRxiv : the preprint server for chemistry最新文献

{"title":"Structural and Data Science-Driven Analysis to Assess Substrate Specificity of Diketopiperazine Reverse Prenyltransferase NotF: Cascade Biocatalytic Synthesis of (–)-Eurotiumin A","authors":"Samantha P. Kelly, V. Shende, A. Flynn, Q. Dan, Yingda Ye, Janet L. Smith, S. Tsukamoto, M. Sigman, D. Sherman","doi":"10.33774/chemrxiv-2021-gmv5j","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-gmv5j","url":null,"abstract":"Prenyltransfer is an early-stage carbon–hydrogen bond (C–H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Towards the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). In the biosynthesis of cytotoxic notoamide metabolites, PT NotF is responsible for catalyzing the first tailoring event of C2 reverse prenyltransfer of brevianamide F (cyclo(L-Trp-L-Pro)). Obtaining a high-resolution crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent exposed substrate binding site, intimating NotF may possess significant substrate promiscuity. To assess the full potential of NotF’s broad substrate selectivity, we synthesized a panel of 30 tryptophanyl DKPs with a suite of sterically and electronically differentiated amino acids, which were selectively prenylated by NotF in often synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library enabled the development of a descriptive statistical model that provided insight into the origins of NotF’s substrate promiscuity. Through this unique approach for understanding enzyme scope, we identified key substrate descriptors such as electrophilicity, size, and flexibility, that govern enzymatic turnover by NotF. Additionally, we demonstrated the ability to couple NotF-catalyzed prenyltransfer with oxidative cyclization using recently characterized flavin monooxygenase, BvnB, from the brevianamide biosynthetic pathway. This one-pot, in vitro biocatalytic cascade proceeds with exceptional substrate recognition, and enabled the first chemoenzymatic synthesis of the marine fungal natural product, (–)-eurotiumin A, in three steps and 60% overall yield.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45885839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An in silico approach for structural and functional annotation of matrix protein of Nipah henipavirus: A protein functional analysis","authors":"Apurbo Kumar Paul, A. S. M. Saikat","doi":"10.33774/chemrxiv-2021-34c3s","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-34c3s","url":null,"abstract":"Nipah henipavirus is an emerging RNA virus with increased mortality threatening global security. In South and Southeast Asia, the Nipah virus has caused numerous disease outbreaks. The matrix protein in Nipah henipavirus has an important role, in connecting the viral envelope with the virus core. For virus assembly, linking the viral envelope with the virus core are very crucial. Through functional and structural explanation evaluations, bioinformatics strategies can help us better understanding of the protein. This investigation aims to allocate the structural and functional annotation of protein. Moreover, the investigation attributes physicochemical parameters, three-dimensional structure, and functional annotation of the protein (QBQ56721.1) applying an in silico perspective. The in silico analysis confirmed the protein's hydrophilic nature, with a secondary structure dominated by alpha (α) helices. Based on several quality assessment methodologies, the tertiary-structure model of the protein has been shown to be reasonably consistent. The functional explanation suggested the protein as a structural protein connected to the viral envelope with the virus core, a protein required for virus assembly. This investigation unleashes the significance of the matrix protein (QBQ56721.1) as a functional protein required for Nipah henipavirus.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49121957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Star-shaped Triazine-derivatives: would they crossbind SARS-CoV-2 spike helices?","authors":"J. coll","doi":"10.33774/chemrxiv-2021-xb6sx-v2","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-xb6sx-v2","url":null,"abstract":"This work describes synthesizable water-soluble Triazine-derivatives computationally crossbinding the S spike helices of Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV-2. The \"spring-loaded switch-folding” (S-SLSF) α-helices included in the S homotrimer top-to-bottom cavity and implicated in viral-host membrane fusion were targeted by star-shaped Trihydroxyl-Triphenyl-Triazines (TTT) leads at subnanomolar binding-scores. Exploration of in silico leads among millions of molecular candidates, included several similar searches, core-replacement, fragment extensions, or convolutional neural network deep-screening combined with hundreds of water-soluble lead-derivatives identified by manual iterations and commercially available building-blocks for chemical synthesis. The lead-derivatives are briefly discussed for in vitro validation and possibilities of fusion inhibition substituting mutations.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45595466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming the Challenges towards Selective C(6)-H Alkylation of 2-Pyridone with Maleimide through Mn(I)-Catalyst: Migration of directing group through cleavage of C-N bond for the formation of all-carbon quaternary carbon center","authors":"Smruti Ranjan Mohanty, Namrata Prusty, S. Banjare, Tanmayee Nanda, P. Ravikumar","doi":"10.33774/chemrxiv-2021-jf8r2-v2","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-jf8r2-v2","url":null,"abstract":"An earth-abundant and inexpensive Mn(I)-catalyzed alkylation of 2-pyridone with maleimide has been reported for the first time, in contrast to previously reported Diels-alder product. The directing group was easily removed after functionalization. Notably, unexpected migration of pyridine ring has been discovered in presence of acetic acid, which also provides unique class of compounds with three different N-heterocycles with an all-carbon quaternary carbon center. Furthermore, single crystal X-ray and HRMS revealed a five-membered manganacycle intermediate. This methodology tolerates a wide variety of functional groups delivering the alkylated products in moderate to excellent yields.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41376302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alteration in H-bond strength affects the stability of codon-anticodon interaction at in-frame UAG stop codon during in vitro translation","authors":"Purnima Mala, Ishu Saraogi","doi":"10.33774/chemrxiv-2021-zr8nt-v2","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-zr8nt-v2","url":null,"abstract":"We have studied the decoding ability of a non-standard nucleobase modified tRNA for non-natural amino acid mutagenesis. The insertion of 2, 6-diaminopurine (D) base at the 3rd position of a tRNA anticodon enabled us to evaluate the effect of an additional hydrogen bond during translation. The presence of D at the tRNA anticodon led to stabilization of the codon-anticodon interaction due to an additional H-bond between the N2-exocyclic amine of D and the C2 carbonyl group of uracil during protein translation. While decoding UAG codons using stop codon suppression methodology, the enhanced codon-anticodon interaction improved codon readthrough and synthesis of modified protein with a non-natural amino acid at multiple sites. Our findings imply that the number of hydrogen bonds at the tRNA-mRNA duplex interface is an important criterion during mRNA decoding and improves protein translation at multiple UAG stop sites. This work provides valuable inputs towards improved non-natural amino acid mutagenesis for creating functional proteins.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48111960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MolAR: Bringing Chemical Structures to Life with Augmented Reality and Machine Learning","authors":"Sukolsak Sakshuwong, Hayley Weir, U. Raucci, T. Martínez","doi":"10.33774/chemrxiv-2021-jnpgl","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-jnpgl","url":null,"abstract":"Visualizing three-dimensional molecular structures is crucial to understanding and predicting their chemical behavior. Existing visualization software, however, can be cumbersome to use, and, for many, hand-drawn skeletal structures remain the preferred method of chemical communication. Although convenient, the static, two-dimensional nature of these drawings can be misleading in conveying the molecule’s 3D structure, not to mention that dynamic movement is completely disregarded. Here, we combine machine learning and augmented reality (AR) to develop MolAR, an immersive mobile application for visualizing molecules in real-world scenes. The application uses deep learning to recognize hand-drawn hydrocarbons structures which it converts into interactive 3D molecules in AR. Users can also “hunt” for chemicals in food and drink to uncover molecules in their real-life environment. A variety of interesting molecules are pre-loaded into the application, and users can visualize molecules in PubChem by providing their name or SMILES string and proteins in the Protein Data Bank by providing their PDB ID. MolAR was designed to be used in both research and education settings, providing an almost barrierless platform to visualize and interact with 3D molecular structures in a uniquely immersive way.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69678773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COVID-19: Invades Erythrocytes through Plasmodium Falciparum Antigen and Complement-Like System (preprint)","authors":"L. Wenzhong","doi":"10.33774/CHEMRXIV-2021-B4C8B","DOIUrl":"https://doi.org/10.33774/CHEMRXIV-2021-B4C8B","url":null,"abstract":"Malaria symptoms are very similar to those of COVID-19, and infections can be symptomatic or asymptomatic. Common immunodominant epitopes are shared by the SARS-CoV-2 proteins and the Plasmodium falciparum antigen. Through bioinformatics methods such as domain search, this study discovered that the S, ORF3a proteins contained Plasmodium antigens rich in tryptophan and threonine. ORF3a, ORF8, S, and N and others also had more extended autotransporter domains. The Plasmodium antigen of S protein contained a C1q domain capable of binding to the complement receptor 1 on the red blood cell membrane. ORF3a contained the Plasmodium antigen EBA-175 domain, which was capable of binding to glycophorin A on the red blood cell membrane. S and ORF3a were bound to band 4.1 to anchor on the erythrocyte membrane skeleton, respectively. The Membrane attack complex component of the S protein formed fusion pores on the red blood cell membrane. Then it injected viral genetic material into the mature red blood cell. ORF3a used a thiol-activated cytolysin domain to create hemolytic pores in the red blood cell membrane. The coagulation factor calcium ions were involved in the red blood cell invasion process. The invasion would have no discernible hemolysis or hypoxia reactions. According to the Plasmodium antigen type for SARS-COV-2, the blood cells of people with blood types A and Knops were susceptible to attack by SARS-COV-2 virus proteins.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48695877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A scalable galvanic approach to microswimmer synthesis","authors":"Maximilian R. Bailey, Nico Reichholf, Anna Flechsig, F. Grillo, L. Isa","doi":"10.33774/chemrxiv-2021-4fmmn","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-4fmmn","url":null,"abstract":"Microswimmers are small particles capable of converting available energy sources into propulsion owing to their compositional asymmetry and are promising for applications ranging from targeted delivery to enhanced mixing at the microscale. However, current fabrication techniques demonstrate limited scalability and/or rely on the excessive use of expensive precursor materials. Here, a scalable Pickering-wax emulsion technique is combined with galvanic electrochemistry, to grow platinum films from copper nanoparticles asymmetrically seeded onto SiOtextsubscript{2} microparticle supports. In this manner, large quantities of Pt-SiOtextsubscript{2} Janus microswimmers are obtained. Utilising copper as a templating material not only reduces synthesis time, material costs, and toxic waste, but also facilitates the further extension of this methodology to a range of functional materials. This electrochemical approach builds upon previous attempts to overcome the current limitations in microswimmer synthesis and offers exciting opportunities for their future development.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43376025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Predictions of Drug Release from Polymeric Long Acting Injectables","authors":"Pauric Bannigan, F. Häse, Matteo Aldeghi, Zeqing Bao, Alán Aspuru-Guzik, C. Allen","doi":"10.33774/chemrxiv-2021-mxrxw","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-mxrxw","url":null,"abstract":"Machine learning is enabling leap-step advances in a number of fields including drug discovery and materials science. The current study explores the application of machine learning to address a critical challenge in pharmaceutical formulation development: the prediction of drug release profiles from polymer-based long-acting injectables. Long acting injectables are considered one of the most promising therapeutic strategies for the treatment of chronic diseases as they can afford improved therapeutic efficacy, safety, and patient compliance. The use of polymer materials in such a drug formulation strategy can offer unparalleled diversity owing to the ability to synthesize materials with a wide range of properties. However, the interplay between multiple parameters, including the physicochemical properties of the drug and polymer, make it near to impossible to predict the performance of these systems a priori. This results in a need to develop and characterize a wide array of formulation candidates through extensive and time-consuming in vitro experimentation. In this study, various neural network architectures are constructed and trained, resulting in accurate predictions of drug release profiles that agree with experimental data. The simplicity with which these broadly applicable machine learning models are identified, using a limited amount of training data, is evidence of the promising potential of data-driven approaches in advanced pharmaceutical formulation development.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46504455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Much Entropy Is Contained in NMR Relaxation Parameters?","authors":"Falk Hoffmann, F. Mulder, Lars V. Schäfer","doi":"10.33774/chemrxiv-2021-l686w","DOIUrl":"https://doi.org/10.33774/chemrxiv-2021-l686w","url":null,"abstract":"Solution-state NMR relaxation experiments are the cornerstone to study internal protein dynamics at an atomic resolution on time scales that are faster than the overall rotational tumbling time τR. Since the motions described by NMR relaxation parameters are connected to thermodynamic quantities like conformational entropies, the question arises how much of the total entropy is contained within this tumbling time. Using all-atom molecular dynamics simulations of the T4 lysozyme, we found that entropy buildup is rather fast for the backbone, such that the majority of the entropy is indeed contained in the short-time dynamics. In contrast, the contribution of the slow dynamics of side chains on time scales beyond τR on the side-chain conformational entropy is significant and should be taken into account for the extraction of accurate thermodynamic properties.","PeriodicalId":72565,"journal":{"name":"ChemRxiv : the preprint server for chemistry","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69679366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}