Generalized biomolecular modeling and design with RoseTTAFold All-Atom

Science, Journal Year: 2024, Volume and Issue: 384(6693)

Published: March 7, 2024

Deep-learning methods have revolutionized protein structure prediction and design but are presently limited to protein-only systems. We describe RoseTTAFold All-Atom (RFAA), which combines a residue-based representation of amino acids DNA bases with an atomic all other groups model assemblies that contain proteins, nucleic acids, small molecules, metals, covalent modifications, given their sequences chemical structures. By fine-tuning on denoising tasks, we developed RFdiffusion (RFdiffusionAA), builds structures around molecules. Starting from random distributions acid residues surrounding target designed experimentally validated, through crystallography binding measurements, proteins bind the cardiac disease therapeutic digoxigenin, enzymatic cofactor heme, light-harvesting molecule bilin.

Language: Английский

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 2, 2023

Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on backbones amino acid side chains proteins and expand diversity proteins, which provides basis for emergence organismal complexity. To date, more than 650 types protein modifications, such as most well-known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short-chain long-chain acylation redox irreversible have been described, inventory is still increasing. By changing conformation, localization, activity, stability, charges, interactions with other biomolecules, PTMs ultimately alter phenotypes biological processes cells. The homeostasis important human health. Abnormal may cause changes in properties loss functions, are closely related occurrence development various diseases. In this review, we systematically introduce characteristics, regulatory mechanisms, functions health addition, therapeutic prospects diseases by targeting associated enzymes also summarized. This work will deepen understanding promote discovery diagnostic prognostic markers drug targets

Language: Английский

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dbPTM in 2022: an updated database for exploring regulatory networks and functional associations of protein post-translational modifications

Nucleic Acids Research, Journal Year: 2021, Volume and Issue: 50(D1), P. D471 - D479

Published: Oct. 13, 2021

Protein post-translational modifications (PTMs) play an important role in different cellular processes. In view of the importance PTMs functions and massive data accumulated by rapid development mass spectrometry (MS)-based proteomics, this paper presents update dbPTM with over 2 777 000 PTM substrate sites obtained from existing databases manual curation literature, which more than 235 entries are experimentally verified. This has manually curated 42 new modification types that were not included previous version. Due to increasing number studies on mechanism past few years, a great deal upstream regulatory proteins have been revealed. The updated thus collates information merges them into protein-protein interaction network. To enhance understanding association between molecular functions/cellular processes, functional annotations integrated database. addition, PTM-related resources, including annotation prediction tools also renewed. Overall, update, we would like provide users most abundant comprehensive proteins. is now freely accessible at https://awi.cuhk.edu.cn/dbPTM/.

Language: Английский

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E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2022, Volume and Issue: 1877(3), P. 188736 - 188736

Published: May 1, 2022

Language: Английский

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Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 27, 2023

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.

Language: Английский

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Transformer-based deep learning for predicting protein properties in the life sciences

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Jan. 18, 2023

Recent developments in deep learning, coupled with an increasing number of sequenced proteins, have led to a breakthrough life science applications, particular protein property prediction. There is hope that learning can close the gap between proteins and known properties based on lab experiments. Language models from field natural language processing gained popularity for predictions new computational revolution biology, where old prediction results are being improved regularly. Such learn useful multipurpose representations large open repositories sequences be used, instance, predict properties. The growing quickly because class model-the Transformer model. We review recent use large-scale applications predicting characteristics how such used predict, example, post-translational modifications. shortcomings other explain proven very promising way unravel information hidden amino acids.

Language: Английский

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Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(2)

Published: Jan. 25, 2022

Abstract Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering structure and functions proteins. The action most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination glycosylation is well documented. A less explored protein PTM, conversion peptidylarginine to citrulline, subject this review. process citrullination catalysed by deiminases (PADs), family conserved enzymes expressed in variety human tissues. Accumulating evidence suggest that plays significant role regulating cellular gene expression affecting multitude pathways modulating chromatin status. Here, we will discuss biochemical nature arginine citrullination, enzymatic machinery behind it also provide information on pathological consequences development inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis COVID-19), cancer thromboembolism. Finally, developments inhibitors against recent clinical trials providing promising therapeutic approach disease targeting are discussed.

Language: Английский

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The molecular athlete: exercise physiology from mechanisms to medals

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(3), P. 1693 - 1787

Published: Jan. 5, 2023

Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels endurance strength elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding signal integration, interpretation, output coordination cellular molecular mechanisms that govern plasticity across this continuum is incomplete. As such, training methods their application largely rely on “trial-and-error” approach, experience practices successful coaches often providing bases for “post hoc” scientific enquiry research. This review provides synopsis morphological functional changes along underlying adaptation endurance- resistance-based training. These traits are placed in context innate genetic interindividual differences performance, special consideration given aging athletes. Collectively, we provide comprehensive overview response different modes how such adaptations translate “molecules medals.”

Language: Английский

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A review on antimicrobial peptides databases and the computational tools

Database, Journal Year: 2022, Volume and Issue: 2022

Published: Jan. 1, 2022

Abstract Antimicrobial Peptides (AMPs) have been considered as potential alternatives for infection therapeutics since antibiotic resistance has raised a global problem. The AMPs are group of natural peptides that play crucial role in the immune system various organisms features such short length and efficiency against microbes. Importantly, they represented low toxicity mammals which makes them candidates peptide-based drugs. Nevertheless, discovery is accompanied by several issues associated with labour-intensive time-consuming wet-lab experiments. During last decades, numerous studies conducted on investigation AMPs, either or synthetic type, relevant data recently available many databases. Through advancement computational methods, great number AMP obtained from publicly accessible databanks, valuable resources mining patterns to design new models prediction. However, due current flaws assessing more interrogations warranted accurate evaluation/analysis. Considering diversity newly reported ones, an improvement Machine Learning algorithms crucial. In this review, we aim provide information about different types their mechanism action landscape databases tools collect beneficial prediction model active AMPs.

Language: Английский

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Applications of Tandem Mass Spectrometry (MS/MS) in Protein Analysis for Biomedical Research

Molecules, Journal Year: 2022, Volume and Issue: 27(8), P. 2411 - 2411

Published: April 8, 2022

Mass Spectrometry (MS) allows the analysis of proteins and peptides through a variety methods, such as Electrospray Ionization-Mass (ESI-MS) or Matrix-Assisted Laser Desorption (MALDI-MS). These methods allow identification mass protein peptide intact molecules peptide-mass fingerprinting generated upon enzymatic digestion. Tandem spectrometry (MS/MS) fragmentation to determine amino acid sequence (top-down middle-down proteomics) (bottom-up proteomics). Furthermore, tandem also post-translational modifications (PTMs) peptides. Here, we discuss application MS/MS in biomedical research, indicating specific examples for their PTMs relevant biomarkers diagnostic therapy.

Language: Английский

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