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

Journal of Chemical Information and Modeling, Год журнала: 2023, Номер 63(5), С. 1413 - 1428

Опубликована: Фев. 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.

Язык: Английский

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Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Viruses, Год журнала: 2023, Номер 15(5), С. 1143 - 1143

Опубликована: Май 10, 2023

Evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity for ACE2, conformational plasticity, protein stability allosteric modulation. In this study, we systematically characterize dynamics, structural affinities SARS-CoV-2 Spike complexes with host receptor ACE2 BA.2, BA.2.75, XBB.1 XBB.1.5 variants. We combined multiscale molecular simulations dynamic analysis interactions together ensemble-based mutational scanning residues network modeling epistatic interactions. This multifaceted computational study characterized mechanisms identified energetic hotspots mediate predicted increased enhanced BA.2.75 complexes. The results a mechanism driven spatially localized group centers, while allowing functionally beneficial neutral mutations in other interface positions. A network-based community model contributions is proposed revealing key role R498 Y501 mediating community-based couplings sites compensatory dynamics changes. also showed convergent evolutionary hotspot F486 modulate not only local but rewire global communities region F486P mutation to restore both variant which may explain growth advantages over variant. are consistent broad range rationalizing roles form coordinated enabling balance tradeoffs shaping up complex landscape virus transmissibility.

Язык: Английский

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The value of protein allostery in rational anticancer drug design: an update

Expert Opinion on Drug Discovery, Год журнала: 2024, Номер 19(9), С. 1071 - 1085

Опубликована: Июль 28, 2024

Introduction Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from into which ligand dock and do not account for exactly how site is altered. Favorable inhibitors nearby follow nature, mimicking diverse regulation strategies.

Язык: Английский

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Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4955 - 4955

Опубликована: Май 1, 2024

Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite increasing interest and effort in discovering inhibitors viral activity interactions with host receptor ACE2. The challenges modulators proteins are associated diversity cryptic sites complex molecular that can be employed by ligands, including alteration conformational equilibrium protein preferential stabilization specific functional states. In current study, we combine dynamics analysis distinct forms full-length trimers machine-learning-based binding pocket detection ensemble-based ligand docking free energy to characterize potential determine structural energetic determinants inhibition a series experimentally validated molecules. results demonstrate good agreement between computational experimental affinities, providing support predicted modes suggesting key formed ligands elicit observed inhibition. We establish known molecules, indicating mechanism modulation targeting hinges inter-protomer movements blocking changes closed open trimer forms. this study combining states rigorous enables robust characterization modes, identification hotspots, prediction affinities modulators, which is consistent data. This suggested adaptability bound conformations both play enable efficient interfere changes.

Язык: Английский

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Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

Viruses, Год журнала: 2023, Номер 15(10), С. 2009 - 2009

Опубликована: Сен. 27, 2023

A significant body of experimental structures SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity protein emergence druggable binding pockets. Understanding interplay conformational dynamics changes induced by Omicron identification cryptic dynamic pockets in S is paramount importance as exploring broad-spectrum antiviral agents to combat emerging imperative. In current study, we explore landscapes characterize universe multiple open closed functional states variants. By using combination atomistic simulations, network analysis, an allostery-guided screening ensembles conformations, identified all experimentally known allosteric sites discovered variant-specific differences distribution trimers. This study provided structural characterization predicted captured sites, revealing critical role modulating cross-talk between sites. We found that mutational variant can induce remodeling stabilization pocket N-terminal domain, while this drastically altered may no longer be available ligand variant. Our results site receptor-binding domain remains stable ranks most favorable but could become fragmented less probable conformations. also uncovered several formed at inter-domain inter-protomer interface, including regions S2 subunit stem helix region, which are consistent with residues transitions antibody recognition. The particularly understanding features proteins, well effects Omicron-variant-specific modulation preferential exploration present new previously underappreciated opportunity therapeutic interventions through conformation-selective targeting involved changes.

Язык: Английский

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Computational Investigation of Selected Spike Protein Mutations in SARS-CoV-2: Delta, Omicron, and Some Circulating Subvariants

Pathogens, Год журнала: 2023, Номер 13(1), С. 10 - 10

Опубликована: Дек. 21, 2023

Among the multiple SARS-CoV-2 variants recently reported, Delta variant has generated most perilous and widespread effects. Another variant, Omicron, been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations numbers much larger than those of predecessor variants. In this report, author discussed some essential structural aspects time-based structure changes a selected set within The expected impact point protein’s receptor-binding domain (RBD) S1 these are examined. Additionally, RBDs more emerged subvariants BA.4, BA.5, BA.2.12.1 discussed. Within latter group, BA.5 represents prevalent form globally until recently. This computational work also briefly explores temporal mutation profile currently circulating interest (VOIs), under monitoring (VUMs), being monitored (VBMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB, XBF, EG.5 (or Eris), BA.2.86 Pirola). It is that data can facilitate tasks identifying drug targets neutralizing antibodies evolving variants/subvariants SARS-CoV-2.

Язык: Английский

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Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages : Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 22, 2023

Abstract The evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity for ACE2, conformational plasticity, protein stability allosteric modulation. In this study, we systematically characterize dynamics, affinities SARS-CoV-2 Spike complexes with host receptor ACE2 BA.2, BA.2.75, XBB.1 XBB.1.5 variants. We combined multiscale molecular simulations dynamic analysis interactions together ensemble-based mutational scanning residues network modeling epistatic interactions. This multifaceted computational study characterized mechanisms identified energetic hotspots mediate predicted increased enhanced BA.2.75 complexes. results a mechanism driven spatially localized group centers, while allowing functionally beneficial neutral mutations in other interface positions. A network-based community model non-additive contributions is proposed revealing key role R498 Y501 mediating community-based couplings sites compensatory dynamics changes. also showed convergent hotspot F486 modulate not only local but rewire global communities region F486P mutation to restore both variant which may explain growth advantages over variant. are consistent broad range rationalizing roles form coordinated enabling balance tradeoffs shaping up complex landscape virus transmissibility.

Язык: Английский

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Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers: Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6642 - 6642

Опубликована: Апрель 2, 2023

Evolutionary and functional studies have suggested that the emergence of Omicron variants can be determined by multiple fitness tradeoffs including immune escape, binding affinity, conformational plasticity, protein stability, allosteric modulation. In this study, we embarked on a systematic comparative analysis dynamics, electrostatics, allostery in different states spike trimers for BA.1, BA.2, BA.2.75 variants. Using efficient accurate coarse-grained simulations atomistic reconstruction ensembles, examined dynamics agree with recent studies, suggesting are most stable among these A mutational scanning inter-protomer interfaces revealed group conserved structural stability hotspots play key role modulation also involved couplings through local contacts interaction networks sites. The results provided evidence more than BA.2 comparable to BA.1 variant. dynamic network modeling S trimers, showed mediators interactions associated major interconnected along potential communication pathways. increased thermodynamic variant may linked organization modularity residue allows communications between This study plausible rationale mechanism which mutations evolve targeting vulnerable sites adaptability elicit escape while maintaining their control balancing robust hotspots.

Язык: Английский

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Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 26, 2022

Abstract Among the multiple SARS-CoV-2 variants recently reported, Delta variant has generated most perilous and widespread effects. Another variant, Omicron, been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations in numbers much larger than those of predecessor variants. In this report we discuss some essential structural aspects time-based structure changes a selected set within The expected impact multiple-point protein’s receptor-binding domain (RBD) S1 these are examined. Additionally, RBD more emerged subvariants BA.4, BA.5 BA.2.12.1 discussed. Within latter group, represents globally, prevalent form at present time. Temporal mutation profile subvariant BF.7 currently circulating interest (VOI) under monitoring (VUMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB XBF computationally explored here briefly with expectation that data will be helpful to identify drug targets neutralize antibodies evolving variants/subvariants SARS-CoV-2.

Язык: Английский

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Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 1, 2023

Abstract The evolutionary and functional studies suggested that the emergence of Omicron variants can be determined by multiple fitness trade-offs including immune escape, binding affinity, conformational plasticity, protein stability allosteric modulation. In this study, we embarked on a systematic comparative analysis dynamics, electrostatics, allostery in different states spike trimers for BA.1, BA.2, BA.2.75 variants. Using efficient accurate coarse-grained simulations atomistic reconstruction ensembles, examined dynamics agrees with recent studies, suggesting are most stable among these A mutational scanning inter-protomer interfaces revealed group conserved structural hotspots play key role modulation also involved couplings through local contacts interaction networks sites. results provided evidence more than BA.2 comparable to BA.1 variant. dynamic network modeling S showed positions driving long-range signaling associated major inter-connected along potential communication pathways, while sites mutations may often correspond weak spots but coupled networks. presented thermodynamic intimately linked residue organization allows broad ensemble communications which between modulated findings plausible rationale mechanisms evolve balance adaptability order ensure proper tradeoff stability, escape.

Язык: Английский

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