Proteins-Structure Function and Bioinformatics最新文献

{"title":"In Silico Screening, Molecular Dynamics Simulation and Binding Free Energy Identify Single‐Point Mutations That Destabilize p53 and Reduce Binding to DNA","authors":"Shahidul M. Islam, Md. Mehedi Hasan, Jahidul Alam, Anonya Dey, Dylan Molineaux","doi":"10.1002/prot.26747","DOIUrl":"https://doi.org/10.1002/prot.26747","url":null,"abstract":"Considering p53's pivotal role as a tumor suppressor protein, proactive identification and characterization of potentially harmful p53 mutations are crucial before they appear in the population. To address this, four computational prediction tools—SIFT, Polyphen‐2, PhD‐SNP, and MutPred2—utilizing sequence‐based and machine‐learning algorithms, were employed to identify potentially deleterious p53 nsSNPs (nonsynonymous single nucleotide polymorphisms) that may impact p53 structure, dynamics, and binding with DNA. These computational methods identified three variants, namely, C141Y, C238S, and L265P, as detrimental to p53 stability. Furthermore, molecular dynamics (MD) simulations revealed that all three variants exhibited heightened structural flexibility compared to the native protein, especially the C141Y and L265P mutations. Consequently, due to the altered structure of mutant p53, the DNA‐binding affinity of all three variants decreased by approximately 1.8 to 9.7 times compared to wild‐type p53 binding with DNA (14 μM). Notably, the L265P mutation exhibited an approximately ten‐fold greater reduction in binding affinity. Consequently, the presence of the L265P mutation in p53 could pose a substantial risk to humans. Given that p53 regulates abnormal tumor growth, this research carries significant implications for surveillance efforts and the development of anticancer therapies.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Ca2+ Binding Site in Proteins With a Fast and Accurate Method Based on Statistical Mechanics and Analysis of Crystal Structures","authors":"Abdul Basit, Devapriya Choudhury, Pradipta Bandyopadhyay","doi":"10.1002/prot.26743","DOIUrl":"https://doi.org/10.1002/prot.26743","url":null,"abstract":"Predicting the precise locations of metal binding sites within metalloproteins is a crucial challenge in biophysics. A fast, accurate, and interpretable computational prediction method can complement the experimental studies. In the current work, we have developed a method to predict the location of Ca<jats:sup>2+</jats:sup> ions in calcium‐binding proteins using a physics‐based method with an all‐atom description of the proteins, which is substantially faster than the molecular dynamics simulation‐based methods with accuracy as good as data‐driven approaches. Our methodology uses the three‐dimensional reference interaction site model (3D‐RISM), a statistical mechanical theory, to calculate Ca<jats:sup>2+</jats:sup> ion density around protein structures, and the locations of the Ca<jats:sup>2+</jats:sup> ions are obtained from the density. We have taken previously used datasets to assess the efficacy of our method as compared to previous works. Our accuracy is 88%, comparable with the FEATURE program, one of the well‐known data‐driven methods. Moreover, our method is physical, and the reasons for failures can be ascertained in most cases. We have thoroughly examined the failed cases using different structural and crystallographic measures, such as B‐factor, R‐factor, electron density map, and geometry at the binding site. It has been found that x‐ray structures have issues in many of the failed cases, such as geometric irregularities and dubious assignment of ion positions. Our algorithm, along with the checks for structural accuracy, is a major step in predicting calcium ion positions in metalloproteins.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and Biochemical Characterization of Aminoglycoside Nucleotidyltransferase(6)-Ib From Campylobacter fetus subsp. fetus.","authors":"Pranav Nalam, Paul D Cook, Brian A Smith","doi":"10.1002/prot.26745","DOIUrl":"https://doi.org/10.1002/prot.26745","url":null,"abstract":"<p><p>Aminoglycoside antibiotics have played a critical role in the treatment of both Gram-negative and Gram-positive bacterial infections. However, antibiotic resistance has severely compromised the efficacy of aminoglycosides. A leading cause of aminoglycoside resistance is mediated by bacterial enzymes that inactivate these drugs via chemical modification. Aminoglycoside nucleotidyltransferase-6 (ANT(6)) enzymes inactivate streptomycin by transferring an adenyl group from ATP to position 6 on the antibiotic. Despite the clinical significance of this activity, ANT(6) enzymes remain relatively uncharacterized. Here, we report the first high resolution x-ray crystallographic structure of ANT(6)-Ib from Campylobacter fetus subsp. fetus bound with streptomycin. Structural modeling and gel filtration chromatography experiments suggest that the enzyme exists as a dimer in which both subunits contribute to the active site. Moreover, superposition of the ANT(6)-Ib structure with the structurally related enzyme lincosamide nucleotidyltransferase B (LinB) permitted the identification of a putative nucleotide binding site. These data also suggest that residues D44 and D46 coordinate essential divalent metal ions and D102 functions as the catalytic base.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DeepPhoPred: Accurate Deep Learning Model to Predict Microbial Phosphorylation.","authors":"Faisal Ahmed, Alok Sharma, Swakkhar Shatabda, Iman Dehzangi","doi":"10.1002/prot.26734","DOIUrl":"https://doi.org/10.1002/prot.26734","url":null,"abstract":"<p><p>Phosphorylation is a substantial posttranslational modification of proteins that refers to adding a phosphate group to the amino acid side chain after translation process in the ribosome. It is vital to coordinate cellular functions, such as regulating metabolism, proliferation, apoptosis, subcellular trafficking, and other crucial physiological processes. Phosphorylation prediction in a microbial organism can assist in understanding pathogenesis and host-pathogen interaction, drug and antibody design, and antimicrobial agent development. Experimental methods for predicting phosphorylation sites are costly, slow, and tedious. Hence low-cost and high-speed computational approaches are highly desirable. This paper presents a new deep learning tool called DeepPhoPred for predicting microbial phospho-serine (pS), phospho-threonine (pT), and phospho-tyrosine (pY) sites. DeepPhoPred incorporates a two-headed convolutional neural network architecture with the squeeze and excitation blocks followed by fully connected layers that jointly learn significant features from the peptide's structural and evolutionary information to predict phosphorylation sites. Our empirical results demonstrate that DeepPhoPred significantly outperforms the existing microbial phosphorylation site predictors with its highly efficient deep-learning architecture. DeepPhoPred as a standalone predictor, all its source codes, and our employed datasets are publicly available at https://github.com/faisalahm3d/DeepPhoPred.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Issue Information ‐ Table of Content","authors":"","doi":"10.1002/prot.26525","DOIUrl":"https://doi.org/10.1002/prot.26525","url":null,"abstract":"","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142178072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Insight Into the Function of DnaB Helicase in Bacterial DNA Replication.","authors":"Zhiming Zhang, Jiang Chen, Maochun Yao, Ganggang Wang","doi":"10.1002/prot.26746","DOIUrl":"https://doi.org/10.1002/prot.26746","url":null,"abstract":"<p><p>In bacteria, chromosome replication is achieved by the coordinations of more than a dozen replisome enzymes. Replication initiation protein DnaA melts DNA duplex at replication origin (oriC) and forms a replication bubble, followed by loading of helicase DnaB with the help of loader protein DnaC. Then the DnaB helicase unwinds the dsDNA and supports the priming of DnaG and the polymerizing of DNA polymerase. The DnaB helicase functions as a platform coupling unwinding, priming, and polymerizing events. The multiple roles of DnaB helicase are underlined by its distinctive architecture and dynamics conformations. In this review, we will discuss the assembling of DnaB hexamer and the conformational changes upon binding of various partners, DnaB in states of closed dilated (CD), closed constricted (CC), closed helical (CH), and open helical (OH) are discussed. These multiple interfaces among DnaB and partners are potential targets for inhibitors design and novel peptide antibiotics development.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physicochemical Evaluation of Remote Homology in the Twilight Zone.","authors":"Jamie Dennis Dixson, Rajeev Kumar Azad","doi":"10.1002/prot.26742","DOIUrl":"https://doi.org/10.1002/prot.26742","url":null,"abstract":"<p><p>A fundamental problem in the field of protein evolutionary biology is determining the degree and nature of evolutionary relatedness among homologous proteins that have diverged to a point where they share less than 30% amino acid identity yet retain similar structures and/or functions. Such proteins are said to lie within the \"Twilight Zone\" of amino acid identity. Many researchers have leveraged experimentally determined structures in the quest to classify proteins in the Twilight Zone. Such endeavors can be highly time consuming and prohibitively expensive for large-scale analyses. Motivated by this problem, here we use molecular weight-hydrophobicity physicochemical dynamic time warping (MWHP DTW) to quantify similarity of simulated and real-world homologous protein domains. MWHP DTW is a physicochemical method requiring only the amino acid sequence to quantify similarity of related proteins and is particularly useful in determining similarity within the Twilight Zone due to its resilience to primary sequence substitution saturation. This is a step forward in determination of the relatedness among Twilight Zone proteins and most notably allows for the discrimination of random similarity and true homology in the 0%-20% identity range. This method was previously presented expeditiously just after the outbreak of COVID-19 because it was able to functionally cluster ACE2-binding betacoronavirus receptor binding domains (RBDs), a task that has been elusive using standard techniques. Here we show that one reason that MWHP DTW is an effective technique for comparisons within the Twilight Zone is because it can uncover hidden homology by exploiting physicochemical conservation, a problem that protein sequence alignment algorithms are inherently incapable of addressing within the Twilight Zone. Further, we present an extended definition of the Twilight Zone that incorporates the dynamic relationship between structural, physicochemical, and sequence-based metrics.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States.","authors":"Madison K Kuhn, Elizabeth A Proctor","doi":"10.1002/prot.26723","DOIUrl":"10.1002/prot.26723","url":null,"abstract":"<p><p>Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer's disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of ALS-linked M337V mutation on the conformational ensembles of TDP-43_321-340 peptide monomer and dimer.","authors":"Jiyuan Zeng, Yiming Tang, Xuewei Dong, Fangying Li, Guanghong Wei","doi":"10.1002/prot.26482","DOIUrl":"10.1002/prot.26482","url":null,"abstract":"<p><p>The transactive response (TAR) DNA/RNA-binding protein 43 (TDP-43) can self-assemble into both functional stress granules via liquid-liquid phase separation (LLPS) and pathogenic amyloid fibrillary aggregates that are closely linked to amyotrophic lateral sclerosis. Previous experimental studies reported that the low complexity domain (LCD) of TDP-43 plays an essential role in the LLPS and aggregation of the full-length protein, and it alone can also undergo LLPS to form liquid droplets mainly via intermolecular interactions in the 321-340 region. And the ALS-associated M337V mutation impairs LCD's LLPS and facilitates liquid-solid phase transition. However, the underlying atomistic mechanism is not well understood. Herein, as a first step to understand the M337V-caused LLPS disruption of TDP-43 LCD mediated by the 321-340 region and the fibrillization enhancement, we investigated the conformational properties of monomer/dimer of TDP-43_321-340 peptide and its M337V mutant by performing extensive all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations demonstrate that M337V mutation alters the residue regions with high helix/β-structure propensities and thus affects the conformational ensembles of both monomer and dimer. M337V mutation inhibits helix formation in the N-terminal Ala-rich region and the C-terminal mutation site region, while facilitating their long β-sheet formation, albeit with a minor impact on the average probability of both helix structure and β-structure. Further analysis of dimer system shows that M337V mutation disrupts inter-molecular helix-helix interactions and W334-W334 π-π stacking interactions which were reported to be important for the LLPS of TDP-43 LCD, whereas enhances the overall peptide residue-residue interactions and weakens peptide-water interactions, which is conducive to peptide fibrillization. This study provides mechanistic insights into the M337V-mutation-induced impairment of phase separation and facilitation of fibril formation of TDP-43 LCD.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9072657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Tetravalent CD95/Fas Fusion Protein With Superior CD95L/FasL Antagonism.","authors":"Isabell Lang, Oliver Paulus, Olena Zaitseva, Harald Wajant","doi":"10.1002/prot.26741","DOIUrl":"https://doi.org/10.1002/prot.26741","url":null,"abstract":"<p><p>Inhibition of CD95/Fas activation is currently under clinical investigation as a therapy for glioblastoma multiforme and preclinical studies suggest that disruption of the CD95-CD95L interaction could also be a strategy to treat inflammatory and neurodegenerative disorders. Besides neutralizing anti-CD95L/FasL antibodies, mainly CD95ed-Fc, a dimeric Fc fusion protein of the extracellular domain of CD95 (CD95ed), is used to prevent CD95 activation. In view of the fact that full CD95 activation requires CD95L-induced CD95 trimerization and clustering of the resulting liganded CD95 trimers, we investigated whether fusion proteins of the extracellular domain of CD95 with a higher valency than CD95ed-Fc have an improved CD95L-neutralization capacity. We evaluated an IgG1(N297A)-based tetravalent CD95ed fusion protein which was obtained by replacing the variable domains of IgG1(N297A) with CD95ed (CD95ed-IgG1(N297A)) and a hexavalent variant obtained by fusion of CD95ed with a TNC-Fc(DANA) scaffold (CD95ed-TNC-Fc(DANA)) promoting hexamerization. The established N297A and DANA mutations were used to minimize FcγR binding of the constructs under maintenance of neonatal Fc receptor (FcRn) binding. Size exclusion high-performance liquid chromatography indicated effective assembly of CD95ed-IgG1(N297A). More important, CD95ed-IgG1(N297A) was much more efficient than CD95ed-Fc in protecting cells from cell death induction by human and murine CD95L. Surprisingly, despite its hexavalent structure, CD95ed-TNC-Fc(DANA) displayed an at best minor improvement of the capacity to neutralize CD95L suggesting that besides valency, other factors, such as spatial organization and agility of the CD95ed domains, play also a role in neutralization of CD95L trimers by CD95ed fusion proteins. More studies are now required to evaluate the superior CD95L-neutralizing capacity of CD95ed-IgG1(N297A) in vivo.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}