Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Journal of Chemical Information and Modeling, Journal Year: 2023, Volume and Issue: 63(5), P. 1413 - 1428

Published: Feb. 24, 2023

Allosteric mechanisms are commonly employed regulatory tools used by proteins to orchestrate complex biochemical processes and control communications in cells. The quantitative understanding characterization of allosteric molecular events among major challenges modern biology require integration innovative computational experimental approaches obtain atomistic-level knowledge the states, interactions, dynamic conformational landscapes. growing body studies empowered emerging artificial intelligence (AI) technologies has opened up new paradigms for exploring learning universe protein allostery from first principles. In this review we analyze recent developments high-throughput deep mutational scanning functions; applications latest adaptations Alpha-fold structural prediction methods dynamics allostery; frontiers integrating machine enhanced sampling techniques advances systems. We also highlight SARS-CoV-2 spike (S) revealing an important often hidden role regulation driving functional changes, binding interactions with host receptor, escape S which critical viral infection. conclude a summary outlook future directions suggesting that AI-augmented biophysical computer simulation beginning transform toward systematic landscapes, may bring about revolution drug discovery.

Language: Английский

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Recurrent SARS-CoV-2 mutations at Spike D796 evade antibodies from pre-Omicron convalescent and vaccinated subjects

Microbiology Spectrum, Journal Year: 2024, Volume and Issue: 12(2)

Published: Jan. 8, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages of the Omicron variant rapidly became dominant in early 2022 and frequently cause human infections despite vaccination or prior infection with other variants. In addition to antibody-evading mutations receptor-binding domain, features amino acid elsewhere Spike protein; however, their effects generally remain ill defined. The D796Y substitution is present all sub-variants occurs at same site as a mutation (D796H) selected during viral evolution chronically infected patient. Here, we map antibody reactivity linear epitope protein overlapping position 796. We show that antibodies binding this region arise pre-Omicron SARS-CoV-2 convalescent vaccinated subjects but both D796H abrogate binding. These results suggest contributes fitness hosts pre-existing immunity variants by evading targeting site.IMPORTANCESevere has evolved substantially through disease 2019 (COVID-19) pandemic: understanding drivers consequences essential for projecting course pandemic developing new countermeasures. study immunological particular strains find it prevents efficient class raised infection. findings reveal novel consequence poorly understood shed light on evolution.

Language: Английский

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SARS-CoV-2 spike protein in infectivity

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 21 - 56

Published: Jan. 1, 2025

Language: Английский

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Efficient discovery of frequently co-occurring mutations in a sequence database with matrix factorization

PLoS Computational Biology, Journal Year: 2025, Volume and Issue: 21(4), P. e1012391 - e1012391

Published: April 24, 2025

We have developed a robust method for efficiently tracking multiple co-occurring mutations in sequence database. Evolution often hinges on the interaction of several to produce significant phenotypic changes that lead proliferation variant. However, identifying numerous simultaneous across vast database sequences poses computational challenge. Our approach leverages matrix factorization technique automatically and pinpoint subsets positions where co-mutations occur, appearing substantial number within validated our using SARS-CoV-2 receptor-binding domains, comprising approximately seven hundred thousand Spike protein, demonstrating superior performance compared reasonably exhaustive brute-force method. Furthermore, we explore biological significance identified co-mutational (CMPs) their potential impact virus’s evolution functionality, key Delta Omicron variants. This analysis underscores role CMPs understanding evolutionary trajectory. By “birth" “death" CMPs, can elucidate persistence specific groups different viral strains, providing valuable insights into virus’ adaptability thus, possibly aiding vaccine design strategies.

Language: Английский

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New star-shaped ligands generated by evolutionary fitting the Omicron spike inner-cavity

Published: April 25, 2023

Predictions generated by evolutionary docking of star-shaped ligands targeting the prefusion state Omicron variants are described here. For this, one selected molecule previously identified with seeSAR program, was used as parent to randomly generate made-on-demand large children libraries for best fitting spike top-to-bottom inner-cavity DataWarrior subprogram. The docking-scores were consensed AutoDockVina ranks normalized molecular size and hydrophobicity. These explorations new main chemotype improved specificity exceptional nanomolar affinities, predicting aqueous soluble molecules trimeric alpha-helices.

Language: Английский

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SARS-CoV-2 S Mutations: A Lesson from the Viral World to Understand How Human Furin Works

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4791 - 4791

Published: March 1, 2023

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiological agent responsible for worldwide pandemic and has now claimed millions of lives. The virus combines several unusual characteristics an extraordinary ability to spread among humans. In particular, dependence maturation envelope glycoprotein S from Furin enables invasion replication virtually within entire body, since this cellular protease ubiquitously expressed. Here, we analyzed naturally occurring variation amino acids sequence around cleavage site S. We found that grossly mutates preferentially at P positions, resulting in single residue replacements associate with gain-of-function phenotypes specific conditions. Interestingly, some combinations are absent, despite evidence supporting cleavability respective synthetic surrogates. any case, polybasic signature maintained and, as a consequence, preserved. Thus, no escape variants observed population. Overall, SARS-CoV-2 system per se represents outstanding example evolution substrate-enzyme interaction, demonstrating fast-tracked optimization protein stretch towards catalytic pocket. Ultimately, these data disclose important information development drugs targeting Furin-dependent pathogens.

Language: Английский

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Endogenous piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(4), P. 2950 - 2964

Published: April 3, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic, can still infect populations in many countries around globe. The Omicron strain is most mutated variant of SARS-CoV-2. high transmissibility and its ability to evade immunity necessitate a priority study properties order quickly create effective means preventing spread. current research aimed examine silico interaction between PIWI-interacting RNAs (piRNAs) SARS-CoV-2 genome (gRNA) identify endogenous piRNAs propose synthetic with strong antiviral activity for drug development. This used validated bioinformatic approaches regarding more than eight million genome. piRNAs' binding sites (BSs) 5'UTR were located overlapping nucleotide sequences termed clusters BSs. Several BSs have been found nsp3, nsp7, RNA-dependent RNA polymerase, endoRNAse, S surface glycoprotein, ORF7a, nucleocapsid. Sixteen that interact gRNA proposed free energy ranging from -170 kJ/mol -175 kJ/mol, be drugs suppress reproduction

Language: Английский

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Complementary Pocket and Network-Based Approach to Search for Spike Protein Allosteric Pocket Sites

ACS Omega, Journal Year: 2023, Volume and Issue: 8(48), P. 45313 - 45325

Published: Oct. 3, 2023

COVID-19 is a persistent public health concern due to the emergence of more virulent and contagious variants resulting from mutations in spike protein. The protein newer variants, including Delta Omicron, may be less sensitive neutralizing antibodies have favorable binding environment human ACE2 receptor. In interest identifying anti-COVID-19 allosteric drugs, network-based approach based on coarse-grained molecular dynamics (CGMD) simulations, complement pocket-based analysis, used identify possible pathways wild-type, Delta, Omicron BA.1 proteins. Three pockets around 30 Å away spike-ACE2 interface are identified underneath three receptor-binding domain (RBD) chains, which potentially druggable hydrophobicity surface accessibility. Meanwhile, reveals intrinsic changes within coupling between RBD could affect overall communication active site pockets, particular stronger RBDA RBDB for wild type, versus RBDC BA.1. These results subsequent drug discovery studies targeting allosterically as part search drugs toolbox against future pandemics.

Language: Английский

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Is COVID-19 as Lethal as the Spanish Flu? The Australian Experience in 1919 and 2020 and the Role of Nonpharmaceutical Interventions (NPIs)

International Journal of Environmental Research and Public Health, Journal Year: 2024, Volume and Issue: 21(3), P. 261 - 261

Published: Feb. 23, 2024

We conducted a comparative historical study to interrogate Professor Peter Doherty’s warning Australians in April 2020 that ‘COVID-19 is just as lethal the Spanish flu’. identified epicentres of both pandemics, namely, metropolitan Sydney 1919 and Melbourne compared lethality Flu COVID-19 these two cities. Lethality was measured by number rate hospital admissions, death rates, age-specific rates age-standardised mortality (ASMRs). Using measures, we demonstrated strikingly different waves infection, their severity at various points time cumulative impact viruses end our period, i.e., 30 September 2020. Hospital admissions deaths from were more than times higher those for The ASMR per 100,000 population 383 7 COVID-19: former about 55 latter. These results suggest COVID-19. perhaps taken seriously partly explains findings this study. Containing infection threw burden on nonpharmaceutical interventions (NPIs) such ‘protective sequestration’ (quarantine), contact tracing, lockdowns masks. It likely persistent detailed tracing scheme provides best possible explanation why NPIs effective therefore contributed lower pandemic its first year.

Language: Английский

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Endogenous piRNAs Can Interact with Omicron Variant of the SARS-CoV-2 Genome

Published: Feb. 7, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the COVID-19 pandemic still able to infect population in many countries. The Omicron strain is most mutated variant of SARS-CoV-2. high transmissibility and ability evade immunity require a priority study its properties order quickly create effective means preventing it. present work devoted silico interaction piRNAs with genome SARS-CoV-2 (gRNA) identify endogenous propose synthetic antiviral activity for drug development. studies were carried out using proven bioinformatic methods entire more than eight million piRNAs. Binding sites (BSs) 5'UTR located overlapping nucleotide sequences called clusters BSs. Several BSs found nsp3, nsp7, RNA-dependent RNA polymerase, endoRNAse, S surface glycoprotein, ORF7a nucleocapsid. 16 have been proposed interact gRNA free binding energy from -170 kJ/mol -175 kJ/mol, which can be used drugs suppress reproduction

Language: Английский

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