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

The Journal of Chemical Physics, Год журнала: 2022, Номер 157(24)

Опубликована: Дек. 5, 2022

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 coupling 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 crosstalk pocket, regions.

Язык: Английский

---

Frustration-driven allosteric regulation and signal transmission in the SARS-CoV-2 spike omicron trimer structures: a crosstalk of the omicron mutation sites allosterically regulates tradeoffs of protein stability and conformational adaptability

Physical Chemistry Chemical Physics, Год журнала: 2022, Номер 24(29), С. 17723 - 17743

Опубликована: Янв. 1, 2022

Dissecting the regulatory principles underlying function and activity of SARS-CoV-2 spike protein at atomic level is paramount importance for understanding mechanisms virus transmissibility immune escape. In this work, we introduce a hierarchical computational approach atomistic modeling allosteric in Omicron proteins present evidence frustration-based allostery as an important energetic driver conformational changes activation. By examining landscapes residue interaction networks structures, have shown that mutational sites are dynamically coupled form central engine allosterically regulated machinery regulates balance tradeoffs between plasticity, stability, functional adaptability. We found inter-protomer regions hotspot clusters control transitions closed open states. Through perturbation-based diffusion analysis communications states, quantified activation mechanism uncover specific roles mutations. Atomistic reconstruction communication pathways kinetic using Markov transient reveal mutations electrostatic bridges operate network switches could global signal transmission protein. The results study revealed distinct yet complementary mutation hotspots enable modulation structural stability which transmissibility.

Язык: Английский

---

Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(4), С. 2172 - 2172

Опубликована: Фев. 16, 2022

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus resilience mutational escape. In this study, we performed comprehensive computational analysis spike trimer complexes single Nb6, VHH E, complex E/VHH V nanobody combination. We combined coarse-grained all-atom molecular simulations collective dynamics binding free energy scanning, perturbation-response network centrality to examine mechanisms nanobody-induced allosteric modulation cooperativity in these nanobodies. By quantifying energetic determinants protein nanobodies, also examined escaping mutations effect Omicron variant on binding. The scanning supported notion that E484A mutation can significant detrimental result Omicron-induced escape from neutralization. Our findings showed might exploit plasticity specific hotspots generate mutants alter response without compromising activity. showing induce long-range couplings between cryptic epitope ACE2-binding site through broader ensemble communication paths is less dependent mediating centers therefore may be sensitive perturbations functional residues. results suggest affinity communications determined by structurally stable regulatory conformationally adaptable are allosterically coupled collectively control

Язык: Английский

---

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

---

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

---

Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614G Mutant: Conformational Plasticity and Frustration-Induced Allostery as Energetic Drivers of Highly Transmissible Spike Variants

Journal of Chemical Information and Modeling, Год журнала: 2022, Номер 62(8), С. 1956 - 1978

Опубликована: Апрель 4, 2022

The structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role D614G mutation that is shared across many concern (VOCs), suggesting effect this on enhanced virus infectivity transmissibility. recent biophysical provided evidence about multiple conformational substates protein. development a plausible mechanistic model can explain experimental observations from more unified thermodynamic perspective objective current work. In study, we employed efficient accurate coarse-grained simulations trimers together with ensemble-based mutational frustration analysis to characterize dynamics signatures landscapes. By combining local profiling states residue-based scanning stability network allosteric interactions communications, determine patterns sensitivity in regions sites variants. We found may induce considerable adaptability open without compromising folding integrity results suggest mutant employ hinge-shift mechanism which dynamic couplings between site interprotomer hinge modulate interdomain interactions, global mobility change, increased form. This study proposes mutation-induced modulation flexibility energetic at interfaces serve as for regulation proteins.

Язык: Английский

---

Gene Therapy Approaches in HIV Treatment

Infectious diseases, Год журнала: 2024, Номер unknown

Опубликована: Апрель 3, 2024

The search for a cure human immunodeficiency virus (HIV) infection has been persistent challenge in global health. While antiretroviral therapy (ART) significantly improved the prognosis individuals living with HIV, need lifelong treatment and presence of viral reservoirs drug resistance necessitate innovative approaches. Gene emerged as promising avenue HIV treatment, utilizing genetic modification to address complexities virus. This chapter provides comprehensive overview gene approaches treatment. It explores fundamental principles techniques highlights specific challenges posed by HIV. Various strategies, including editing technologies transfer methods, are discussed detail, along their potential advantages limitations. Safety, efficacy, ethical considerations also examined. concludes glimpse into future emphasizing importance interdisciplinary collaboration continued research. aims inspire further exploration harnessing therapy’s transformative quest an cure.

Язык: Английский

---

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

---

Wordom update 2: A user-friendly program for the analysis of molecular structures and conformational ensembles

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 1390 - 1402

Опубликована: Янв. 1, 2023

We present the second update of Wordom, a user-friendly and efficient program for manipulation analysis conformational ensembles from molecular simulations. The actual expands some existing modules adds 21 new to 1 published in 2011. can be divided into three sets that: 1) analyze atomic fluctuations structural communication; 2) explore ion-channel dynamics ionic translocation; 3) compute geometrical indices deformation. Set serves correlations motions, find geometrically stable domains, identify dynamically invariant core, changes domain-domain separation mutual orientation, perform wavelet large-scale simulations, process output principal component fluctuations, functional mode analysis, infer regions mechanical rigidity, overall perturbation response scanning. 2 includes specific ion channels, which serve monitor pore radius as well water or fluxes, measure collective motions like receptor twisting tilting angles. Finally, set 3 tools deformations by computing angles, perimeter, area, volume, β-sheet curvature, radial distribution function, center mass. ring perception module is also included, helpful supramolecular self-assemblies. This places Wordom among most suitable, complete, user-friendly, software biomolecular source code relative documentation are available under GNU general public license at http://wordom.sf.net.

Язык: Английский

---

Computational Analysis of the SARS-CoV-2 RBD–ACE2-Binding Process Based on MD and the 3D-RISM Theory

Journal of Chemical Information and Modeling, Год журнала: 2022, Номер 62(11), С. 2889 - 2898

Опубликована: Май 18, 2022

The binding process of angiotensin-converting enzyme 2 (ACE2) to the receptor-binding domain (RBD) severe acute respiratory syndrome-like coronavirus spike protein was investigated using molecular dynamics simulation and three-dimensional reference interaction-site model theory. results suggested that protein-binding consists a protein–protein approaching step, followed by local structural rearrangement step. In interprotein interaction energy decreased as proteins approached each other, whereas solvation free increased. As approached, glycan ACE2 first established hydrogen bond with RBD. Thereafter, number bonds increased rapidly. because desolvation it its partner. spatial distribution function solvent revealed presence bridged water molecules on RBD–ACE2 interface. Finally, principal component analysis showed pronounced conformational change, there no significant change in

Язык: Английский

---