Protein Science最新文献_第10页

BracketMaker: Visualization and optimization of chemical protein synthesis BracketMaker：化学蛋白质合成的可视化和优化

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5174

Judah L. Evangelista, Michael S. Kay

{"title":"BracketMaker: Visualization and optimization of chemical protein synthesis","authors":"Judah L. Evangelista, Michael S. Kay","doi":"10.1002/pro.5174","DOIUrl":"https://doi.org/10.1002/pro.5174","url":null,"abstract":"Chemical protein synthesis (CPS), in which custom peptide segments of ~20–60 aa are produced by solid‐phase peptide synthesis and then stitched together through sequential ligation reactions, is an increasingly popular technique. The workflow of CPS is often depicted with a “bracket” style diagram detailing the starting segments and the order of all ligation, desulfurization, and/or deprotection steps to obtain the product protein. Brackets are invaluable tools for comparing multiple possible synthetic approaches and serve as blueprints throughout a synthesis. Drawing CPS brackets by hand or in standard graphics software, however, is a painstaking and error‐prone process. Furthermore, the CPS field lacks a standard bracket format, making side‐by‐side comparisons difficult. To address these problems, we developed BracketMaker, an open‐source Python program with built‐in graphic user interface (GUI) for the rapid creation and analysis of CPS brackets. BracketMaker contains a custom graphics engine which converts a text string (a protein sequence annotated with reaction steps, introduced herein as a standardized format for brackets) into a high‐quality vector or PNG image. To aid with new syntheses, BracketMaker's “AutoBracket” tool automatically performs retrosynthetic analysis on a set of segments to draft and rank all possible ligation orders using standard native chemical ligation, protection, and desulfurization techniques. AutoBracket, in conjunction with an improved version of our previously reported Automated Ligator (Aligator) program, provides a pipeline to rapidly develop synthesis plans for a given protein sequence. We demonstrate the application of both programs to develop a blueprint for 65 proteins of the minimal Escherichia coli ribosome.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"19 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanics studies of factors affecting overall rate in cascade reactions: Multi‐enzyme colocalization and environment 影响级联反应总速率因素的分子力学研究：多酶共定位和环境

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5175

Shivansh Kaushik, Ta I Hung, Chia‐en A. Chang

{"title":"Molecular mechanics studies of factors affecting overall rate in cascade reactions: Multi‐enzyme colocalization and environment","authors":"Shivansh Kaushik, Ta I Hung, Chia‐en A. Chang","doi":"10.1002/pro.5175","DOIUrl":"https://doi.org/10.1002/pro.5175","url":null,"abstract":"Millions of years of evolution have optimized many biosynthetic pathways by use of multi‐step catalysis. In addition, multi‐step metabolic pathways are commonly found in and on membrane‐bound organelles in eukaryotic biochemistry. The fundamental mechanisms that facilitate these reaction processes provide strategies to bioengineer metabolic pathways in synthetic chemistry. Using Brownian dynamics simulations, here we modeled intermediate substrate transportation of colocalized yeast–ester biosynthesis enzymes on the membrane. The substrate acetate ion traveled from the pocket of aldehyde dehydrogenase to its target enzyme acetyl‐CoA synthetase, then the substrate acetyl CoA diffused from Acs1 to the active site of the next enzyme, alcohol‐O‐acetyltransferase. Arranging two enzymes with the smallest inter‐enzyme distance of 60 Å had the fastest average substrate association time as compared with anchoring enzymes with larger inter‐enzyme distances. When the off‐target side reactions were turned on, most substrates were lost, which suggests that native localization is necessary for efficient final product synthesis. We also evaluated the effects of intermolecular interactions, local substrate concentrations, and membrane environment to bring mechanistic insights into the colocalization pathways. The computation work demonstrates that creating spatially organized multi‐enzymes on membranes can be an effective strategy to increase final product synthesis in bioengineering systems.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"2 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of EGFR binding hotspots for design of new EGFR inhibitory biologics 分析表皮生长因子受体结合热点，设计新型表皮生长因子受体抑制生物制剂

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5141

Claiborne W. Tydings, Bhuminder Singh, Adam W. Smith, Kaitlyn V. Ledwitch, Benjamin P. Brown, Christine M. Lovly, Allison S. Walker, Jens Meiler

{"title":"Analysis of EGFR binding hotspots for design of new EGFR inhibitory biologics","authors":"Claiborne W. Tydings, Bhuminder Singh, Adam W. Smith, Kaitlyn V. Ledwitch, Benjamin P. Brown, Christine M. Lovly, Allison S. Walker, Jens Meiler","doi":"10.1002/pro.5141","DOIUrl":"https://doi.org/10.1002/pro.5141","url":null,"abstract":"The epidermal growth factor (EGF) receptor (EGFR) is activated by the binding of one of seven EGF‐like ligands to its ectodomain. Ligand binding results in EGFR dimerization and stabilization of the active receptor conformation subsequently leading to activation of downstream signaling. Aberrant activation of EGFR contributes to cancer progression through EGFR overexpression/amplification, modulation of its positive and negative regulators, and/or activating mutations within EGFR. EGFR targeted therapeutic antibodies prevent dimerization and interaction with endogenous ligands by binding the ectodomain of EGFR. However, these antibodies have had limited success in the clinic, partially due to EGFR ectodomain resistance mutations, and are only applicable to a subset of patients with EGFR‐driven cancers. These limitations suggest that alternative EGFR targeted biologics need to be explored for EGFR‐driven cancer therapy. To this end, we analyze the EGFR interfaces of known inhibitory biologics with determined structures in the context of endogenous ligands, using the Rosetta macromolecular modeling software to highlight the most important interactions on a per‐residue basis. We use this analysis to identify the structural determinants of EGFR targeted biologics. We suggest that commonly observed binding motifs serve as the basis for rational design of new EGFR targeted biologics, such as peptides, antibodies, and nanobodies.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"211 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ligand‐induced CaMKIIα hub Trp403 flip, hub domain stacking, and modulation of kinase activity 配体诱导的 CaMKIIα 中枢 Trp403 翻转、枢纽结构域堆叠和激酶活性调节

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5152

Dilip Narayanan, Anne Sofie G. Larsen, Stine Juul Gauger, Ruth Adafia, Rikke Bartschick Hammershøi, Louise Hamborg, Jesper Bruus‐Jensen, Nane Griem‐Krey, Christine L. Gee, Bente Frølund, Margaret M. Stratton, John Kuriyan, Jette Sandholm Kastrup, Annette E. Langkilde, Petrine Wellendorph, Sara M. Ø. Solbak

{"title":"Ligand‐induced CaMKIIα hub Trp403 flip, hub domain stacking, and modulation of kinase activity","authors":"Dilip Narayanan, Anne Sofie G. Larsen, Stine Juul Gauger, Ruth Adafia, Rikke Bartschick Hammershøi, Louise Hamborg, Jesper Bruus‐Jensen, Nane Griem‐Krey, Christine L. Gee, Bente Frølund, Margaret M. Stratton, John Kuriyan, Jette Sandholm Kastrup, Annette E. Langkilde, Petrine Wellendorph, Sara M. Ø. Solbak","doi":"10.1002/pro.5152","DOIUrl":"https://doi.org/10.1002/pro.5152","url":null,"abstract":"γ‐Hydroxybutyric acid (GHB) analogs are small molecules that bind competitively to a specific cavity in the oligomeric CaMKIIα hub domain. Binding affects conformation and stability of the hub domain, which may explain the neuroprotective action of some of these compounds. Here, we describe molecular details of interaction of the larger‐type GHB analog 2‐(6‐(4‐chlorophenyl)imidazo[1,2‐b]pyridazine‐2‐yl)acetic acid (PIPA). Like smaller‐type analogs, PIPA binding to the CaMKIIα hub domain promoted thermal stability. PIPA additionally modulated CaMKIIα activity under sub‐maximal CaM concentrations and ultimately led to reduced substrate phosphorylation. A high‐resolution X‐ray crystal structure of a stabilized CaMKIIα (6x mutant) hub construct revealed details of the binding mode of PIPA, which involved outward placement of tryptophan 403 (Trp403), a central residue in a flexible loop close to the upper hub cavity. Small‐angle X‐ray scattering (SAXS) solution structures and mass photometry of the CaMKIIα wild‐type hub domain in the presence of PIPA revealed a high degree of ordered self‐association (stacks of CaMKIIα hub domains). This stacking neither occurred with the smaller compound 3‐hydroxycyclopent‐1‐enecarboxylic acid (HOCPCA), nor when Trp403 was replaced with leucine (W403L). Additionally, CaMKIIα W403L hub was stabilized to a larger extent by PIPA compared to CaMKIIα hub wild type, indicating that loop flexibility is important for holoenzyme stability. Thus, we propose that ligand‐induced outward placement of Trp403 by PIPA, which promotes an unforeseen mechanism of hub domain stacking, may be involved in the observed reduction in CaMKIIα kinase activity. Altogether, this sheds new light on allosteric regulation of CaMKIIα activity via the hub domain.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"39 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integration of proteomic data with genome‐scale metabolic models: A methodological overview 蛋白质组数据与基因组尺度代谢模型的整合：方法概述

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5150

Farid Zare, Ronan M. T. Fleming

{"title":"Integration of proteomic data with genome‐scale metabolic models: A methodological overview","authors":"Farid Zare, Ronan M. T. Fleming","doi":"10.1002/pro.5150","DOIUrl":"https://doi.org/10.1002/pro.5150","url":null,"abstract":"The integration of proteomics data with constraint‐based reconstruction and analysis (COBRA) models plays a pivotal role in understanding the relationship between genotype and phenotype and bridges the gap between genome‐level phenomena and functional adaptations. Integrating a generic genome‐scale model with information on proteins enables generation of a context‐specific metabolic model which improves the accuracy of model prediction. This review explores methodologies for incorporating proteomics data into genome‐scale models. Available methods are grouped into four distinct categories based on their approach to integrate proteomics data and their depth of modeling. Within each category section various methods are introduced in chronological order of publication demonstrating the progress of this field. Furthermore, challenges and potential solutions to further progress are outlined, including the limited availability of appropriate in vitro data, experimental enzyme turnover rates, and the trade‐off between model accuracy, computational tractability, and data scarcity. In conclusion, methods employing simpler approaches demand fewer kinetic and omics data, consequently leading to a less complex mathematical problem and reduced computational expenses. On the other hand, approaches that delve deeper into cellular mechanisms and aim to create detailed mathematical models necessitate more extensive kinetic and omics data, resulting in a more complex and computationally demanding problem. However, in some cases, this increased cost can be justified by the potential for more precise predictions.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"22 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering and physicochemical characterization of a novel, stable, symmetric bispecific antibody with dual target‐binding using a common light chain 一种新型、稳定、对称的双特异性抗体的工程设计和理化表征--利用共同的轻链实现双目标结合

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5121

Seiji Saito, Makoto Nakayama, Kaori Yamazaki, Yuya Miyamoto, Keiko Hiraishi, Daisuke Tomioka, Sayaka Takagi‐Maeda, Katsuaki Usami, Nobuaki Takahashi, Shinji Nara, Eiichiro Imai

{"title":"Engineering and physicochemical characterization of a novel, stable, symmetric bispecific antibody with dual target‐binding using a common light chain","authors":"Seiji Saito, Makoto Nakayama, Kaori Yamazaki, Yuya Miyamoto, Keiko Hiraishi, Daisuke Tomioka, Sayaka Takagi‐Maeda, Katsuaki Usami, Nobuaki Takahashi, Shinji Nara, Eiichiro Imai","doi":"10.1002/pro.5121","DOIUrl":"https://doi.org/10.1002/pro.5121","url":null,"abstract":"Bispecific antibodies (BsAbs) have emerged as a major class of antibody therapeutics owing to their substantial potential in disease treatment. While several BsAbs have been successfully approved in recent years, ongoing development efforts continue to focus on optimizing various BsAbs tailored to particular antigens and action mechanisms, aiming to achieve favorable physicochemical properties. BsAbs generally encounter challenges due to their unfavorable physicochemical characteristics and poor manufacturing efficiencies, highlighting the need for optimization to achieve reliable productivity and developability. Herein, we describe the development of a novel symmetric BsAb, REGULGENT™ (N‐term/C‐term), comprising two Fab domains, using a common light chain. The heavy chain fragment encoded two antigen‐binding determinants in one chain. The design and production of REGULGENT™ (N‐term/C‐term) are simple owing to the use of the same light chain, which does not induce heavy and light chain mispairing, frequently observed with the asymmetric BsAb format. REGULGENT™ (N‐term/C‐term) exhibited high expression and low aggregation characteristics during cell culture and stress treatment under low pH conditions. Differential scanning calorimetric data indicated that REGULGENT™ molecules had high conformational stability, similar to that of stabilized monoclonal antibodies. Surface plasmon resonance data showed that REGULGENT™ (N‐term/C‐term) could bind to two antigens simultaneously and exhibited a high affinity for two antigens. In summary, the symmetric BsAb format of REGULGENT™ confers its desirable IgG‐like physicochemical properties, thus making it an excellent candidate for commercial development. The findings demonstrate a novel BsAb with substantial development potential for clinical applications.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"14 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mining unique cysteine synthetases and computational study on thoroughly eliminating feedback inhibition through tunnel engineering 挖掘独特的半胱氨酸合成酶，并对通过隧道工程彻底消除反馈抑制进行计算研究

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5160

Shuai Xu, Zong‐Lin Li, Zhi‐Min Li, Hong‐Lai Liu

{"title":"Mining unique cysteine synthetases and computational study on thoroughly eliminating feedback inhibition through tunnel engineering","authors":"Shuai Xu, Zong‐Lin Li, Zhi‐Min Li, Hong‐Lai Liu","doi":"10.1002/pro.5160","DOIUrl":"https://doi.org/10.1002/pro.5160","url":null,"abstract":"L‐cysteine is an essential component in pharmaceutical and agricultural industries, and synthetic biology has made strides in developing new metabolic pathways for its production, particularly in archaea with unique O‐phosphoserine sulfhydrylases (OPSS) as key enzymes. In this study, we employed database mining to identify a highly catalytic activity OPSS from Acetobacterium sp. (AsOPSS). However, it was observed that the enzymatic activity of AsOPSS suffered significant feedback inhibition from the product L‐cysteine, exhibiting an IC50 value of merely 1.2 mM. A semi‐rational design combined with tunnel analysis strategy was conducted to engineer AsOPSS. The best variant, AsOPSSA218R was achieved, totally eliminating product inhibition without sacrificing catalytic efficiency. Molecular docking and molecular dynamic simulations indicated that the binding conformation of AsOPSSA218R with L‐cys was altered, leading to a reduced affinity between L‐cysteine and the active pocket. Tunnel analysis revealed that the AsOPSSA218R variant reshaped the landscape of the tunnel, resulting in the construction of a new tunnel. Furthermore, random acceleration molecular dynamics simulation and umbrella sampling simulation demonstrated that the novel tunnel improved the suitability for product release and effectively separated the interference between the product release and substrate binding processes. Finally, more than 45 mM of L‐cysteine was produced in vitro within 2 h using the AsOPSSA218R variant. Our findings emphasize the potential for relieving feedback inhibition by artificially generating new product release channels, while also laying an enzymatic foundation for efficient L‐cysteine production.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"82 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Benchmarking reverse docking through AlphaFold2 human proteome 通过 AlphaFold2 人类蛋白质组进行反向对接基准测试

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5167

Qing Luo, Sheng Wang, Hoi Yeung Li, Liangzhen Zheng, Yuguang Mu, Jingjing Guo

{"title":"Benchmarking reverse docking through AlphaFold2 human proteome","authors":"Qing Luo, Sheng Wang, Hoi Yeung Li, Liangzhen Zheng, Yuguang Mu, Jingjing Guo","doi":"10.1002/pro.5167","DOIUrl":"https://doi.org/10.1002/pro.5167","url":null,"abstract":"Predicting the binding of ligands to the human proteome via reverse‐docking methods enables the understanding of ligand's interactions with potential protein targets in the human body, thereby facilitating drug repositioning and the evaluation of potential off‐target effects or toxic side effects of drugs. In this study, we constructed 11 reverse docking pipelines by integrating site prediction tools (PointSite and SiteMap), docking programs (Glide and AutoDock Vina), and scoring functions (Glide, Autodock Vina, RTMScore, DeepRMSD, and OnionNet‐SFCT), and then thoroughly benchmarked their predictive capabilities. The results show that the Glide_SFCT (PS) pipeline exhibited the best target prediction performance based on the atomic structure models in AlphaFold2 human proteome. It achieved a success rate of 27.8% when considering the top 100 ranked prediction. This pipeline effectively narrows the range of potential targets within the human proteome, laying a foundation for drug target prediction, off‐target assessment, and toxicity prediction, ultimately boosting drug development. By facilitating these critical aspects of drug discovery and development, our work has the potential to ultimately accelerate the identification of new therapeutic agents and improve drug safety.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"5 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AlzDiscovery: A computational tool to identify Alzheimer's disease‐causing missense mutations using protein structure information AlzDiscovery：利用蛋白质结构信息识别阿尔茨海默病致病错义突变的计算工具

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5147

Qisheng Pan, Georgina Becerra Parra, Yoochan Myung, Stephanie Portelli, Thanh Binh Nguyen, David B. Ascher

{"title":"AlzDiscovery: A computational tool to identify Alzheimer's disease‐causing missense mutations using protein structure information","authors":"Qisheng Pan, Georgina Becerra Parra, Yoochan Myung, Stephanie Portelli, Thanh Binh Nguyen, David B. Ascher","doi":"10.1002/pro.5147","DOIUrl":"https://doi.org/10.1002/pro.5147","url":null,"abstract":"Alzheimer's disease (AD) is one of the most common forms of dementia and neurodegenerative diseases, characterized by the formation of neuritic plaques and neurofibrillary tangles. Many different proteins participate in this complicated pathogenic mechanism, and missense mutations can alter the folding and functions of these proteins, significantly increasing the risk of AD. However, many methods to identify AD‐causing variants did not consider the effect of mutations from the perspective of a protein three‐dimensional environment. Here, we present a machine learning‐based analysis to classify the AD‐causing mutations from their benign counterparts in 21 AD‐related proteins leveraging both sequence‐ and structure‐based features. Using computational tools to estimate the effect of mutations on protein stability, we first observed a bias of the pathogenic mutations with significant destabilizing effects on family AD‐related proteins. Combining this insight, we built a generic predictive model, and improved the performance by tuning the sample weights in the training process. Our final model achieved the performance on area under the receiver operating characteristic curve up to 0.95 in the blind test and 0.70 in an independent clinical validation, outperforming all the state‐of‐the‐art methods. Feature interpretation indicated that the hydrophobic environment and polar interaction contacts were crucial to the decision on pathogenic phenotypes of missense mutations. Finally, we presented a user‐friendly web server, AlzDiscovery, for researchers to browse the predicted phenotypes of all possible missense mutations on these 21 AD‐related proteins. Our study will be a valuable resource for AD screening and the development of personalized treatment.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"22 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of artificial photosystems based on designed proteins for mechanistic insights into photosynthesis 开发基于设计蛋白质的人工光合系统，深入了解光合作用的机理

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5164

Gonzalo Pérez Serrano, Claudia F. Echavarría, Sara H. Mejias

{"title":"Development of artificial photosystems based on designed proteins for mechanistic insights into photosynthesis","authors":"Gonzalo Pérez Serrano, Claudia F. Echavarría, Sara H. Mejias","doi":"10.1002/pro.5164","DOIUrl":"https://doi.org/10.1002/pro.5164","url":null,"abstract":"This review aims to provide an overview of the progress in protein‐based artificial photosystem design and their potential to uncover the underlying principles governing light‐harvesting in photosynthesis. While significant advances have been made in this area, a gap persists in reviewing these advances. This review provides a perspective of the field, pinpointing knowledge gaps and unresolved challenges that warrant further inquiry. In particular, it delves into the key considerations when designing photosystems based on the chromophore and protein scaffold characteristics, presents the established strategies for artificial photosystems engineering with their advantages and disadvantages, and underscores the recent breakthroughs in understanding the molecular mechanisms governing light‐harvesting, charge separation, and the role of the protein motions in the chromophore's excited state relaxation. By disseminating this knowledge, this article provides a foundational resource for defining the field of bio‐hybrid photosystems and aims to inspire the continued exploration of artificial photosystems using protein design.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"2 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0