Probing Conformational Landscapes and Mechanisms of Allosteric Communication in the Functional States of the ABL Kinase Domain Using Multiscale Simulations and Network-Based Mutational Profiling of Allosteric Residue Potentials

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 2, 2022

Abstract In the current study, multiscale simulation approaches and dynamic network methods are employed to examine energetic details of conformational landscapes allosteric interactions in ABL kinase domain that determine functions. Using a plethora synergistic computational approaches, we elucidate how transitions between active inactive states can employ regulatory switches modulate intramolecular communication networks ATP site, substrate binding region, pocket. A perturbation-based approach implements mutational profiling residue propensities communications is proposed. Consistent with biophysical experiments, results reveal functionally significant shifts interaction which preferential paths site regions state become suppressed closed form, turn features favorable couplings By integrating atomistic simulations dimensionality reduction Markov models analyze mechanistic role macrostates characterize kinetic states. network-based scanning propensities, this study provides comprehensive analysis long-range identifies conserved hotspots activity cross-talk pocket, regions.

Language: 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), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 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.

Language: 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), Journal Year: 2022, Volume and Issue: unknown

Published: June 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.

Language: 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, Journal Year: 2022, Volume and Issue: 12(7), P. 964 - 964

Published: July 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.

Language: 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), Journal Year: 2023, Volume and Issue: unknown

Published: May 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.

Language: Английский

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