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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Quantitative Characterization and Prediction of the Binding Determinants and Immune Escape Hotspots for Groups of Broadly Neutralizing Antibodies Against Omicron Variants: Atomistic Modeling of the SARS-CoV-2 Spike Complexes with Antibodies

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 20, 2024

Abstract The growing body of experimental and computational studies suggested that the cross-neutralization antibody activity against Omicron variants may be driven by balance tradeoff multiple energetic factors interaction contributions evolving escape hotspots involved in antigenic drift convergent evolution. However, dynamic details quantifying contribution these factors, particularly balancing nature specific interactions formed antibodies with epitope residues remain scarcely characterized. In this study, we performed molecular dynamics simulations, ensemble-based deep mutational scanning SARS-CoV-2 spike binding free energy computations for two distinct groups broadly neutralizing : E1 group (BD55-3152, BD55-3546 BD5-5840) F3 (BD55-3372, BD55-4637 BD55-5514). Using approaches, examine determinants which potent can largely evade immune resistance. Our analysis revealed emergence a small number positions correspond to R346 K444 strong van der Waals act synchronously leading large contribution. According our results, Abs effectively exploit hotspot clusters hydrophobic sites critical functions along selective complementary targeting positively charged are important ACE2 binding. Together conserved epitopes, lead expanded neutralization breadth resilience shift associated viral results study demonstrate excellent qualitative agreement between predicted mutations respect latest experiments on average scores. We argue epitopes leverage stability binding, while tend emerge synergistically electrostatic interactions.

Язык: Английский

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Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

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

Опубликована: Июнь 19, 2022

Abstract In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, perturbation-based network profiling allosteric interactions in SARS-Cov-2 Spike complexes with a panel cross-reactive ultra-potent single antibodies (B1-182.1 A23-58.1) as well antibody combinations (A19-61.1/B1-182.1 A19-46.1/B1-182.1). Using approach, quantify local global effects mutations complexes, identify structural centers, characterize binding energy hotspots predict control points long-range communications. Conformational dynamics distance fluctuation analysis revealed antibody-specific signatures spike that can dictate pattern escape. By employing an integrated conformational energetics, found potent efficiently neutralize Omicron variant form dominant hotpots conserved centers which may be restricted by requirements folding to host receptor. The results show energetics SARS-CoV-2 ultrapotent are tolerant constellation mutations. A network-based perturbation approach for residues potentials how modulate identified vulnerable sites This study suggested mechanism specific escape mutants not solely determined interaction changes but driven complex balance tradeoffs between different factors including impact on stability, strength, fidelity signaling.

Язык: Английский

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Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

Biomolecules, Год журнала: 2022, Номер 12(7), С. 964 - 964

Опубликована: Июль 10, 2022

In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, perturbation-based network profiling allosteric interactions in SARS-CoV-2 spike complexes with a panel cross-reactive ultra-potent single antibodies (B1-182.1 A23-58.1) as well antibody combinations (A19-61.1/B1-182.1 A19-46.1/B1-182.1). Using approach, quantify local global effects mutations complexes, identify centers, characterize binding energy hotspots, predict control points long-range communications. Conformational dynamics distance fluctuation analysis revealed antibody-specific signatures flexibility that can affect pattern escape. A network-based perturbation approach for residue potentials how modulate identified form vulnerable sites The results show energetics ultrapotent are tolerant to effect Omicron mutations, which may be related their neutralization efficiency. By employing an integrated conformational dynamics, energetics, interactions, found neutralize variant mediate dominant hotpots conserved centers restricted by requirements folding host receptor. This study suggested mechanism patterns escape mutants not solely determined interaction changes but associated balance tradeoffs multiple factors, including stability, affinity, interactions.

Язык: Английский

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Probing Conformational Landscapes of Binding and Allostery in the SARS-CoV-2 Omicron Variant Complexes Using Microsecond Atomistic Simulations and Perturbation-Based Profiling Approaches: Hidden Role of Omicron Mutations as Modulators of Allosteric Signaling and Epistatic Relationships

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

Опубликована: Май 4, 2023

In this study, we systematically examine the conformational dynamics, binding and allosteric communications in Omicron BA.1, BA.2, BA.3 BA.4/BA.5 complexes with ACE2 host receptor using molecular dynamics simulations perturbation-based network profiling approaches. Microsecond atomistic provided a detailed characterization of landscapes revealed increased thermodynamic stabilization BA.2 variant which is contrasted variants inducing significant mobility complexes. Using ensemble-based mutational scanning interactions, identified affinity structural stability hotspots Perturbation response network-based approaches probed effect on communications. The results analysis specific roles mutations as "plastic evolutionary adaptable" modulators allostery are coupled to major regulatory positions through interaction networks. Through perturbation residue potentials complexes, performed background original strain, that key N501Y Q498R could mediate interactions epistatic couplings. Our suggested synergistic role these controlling stability, can enable for compensatory balance fitness tradeoffs conformationally adaptable immune-escape mutations. integrative computational approaches, study provides systematic effects thermodynamics, signaling receptor. findings support mechanism evolve adaptability order ensure proper tradeoff between immune escape.

Язык: Английский

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