Aria Gheeraert

Université Paris Cité

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Ivan Rivalta

Laboratoire de Chimie

Víctor S. Batista

Yale University

Laurent Vuillon

Université Savoie Mont Blanc

Federica Maschietto

Yale University

Tatiana Galochkina

Université Paris Cité

Bernard R. Brooks

National Heart Lung and Blood Institute

Apala Chaudhuri

University of Pennsylvania

Serge Pérez

Centre de Recherches sur les Macromolécules Végétales

Florentina Tofoleanu

Yale University

Uriel N. Morzan

Fundación Ciencias Exactas y Naturales

Cooperative Institutions

Centre National de la Recherche Scientifique

Inserm

Université Paris Cité

Yale University

Université Claude Bernard Lyon 1

Université de Lorraine

Laboratoire Lorrain de Recherche en Informatique et ses Applications

École Normale Supérieure de Lyon

Universitat de Barcelona

Biologie Intégrée du Globule Rouge

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The Heat is On: Temperature Increase Mimics Allosteric Signaling in Imidazole-Glycerol Phosphate Synthase

Research Square (Research Square) (2022)

Federica Maschietto Uriel N. Morzan Florentina Tofoleanu Aria Gheeraert Apala Chaudhuri

Abstract Allosteric drugs have the potential to revolutionize biomedicine due to their enhanced selectivity and protection against overdosage. However, we need to better understand allosteric mechanisms in order to fully harness their potential in drug discovery. In this study, molecular dynamics simulations and nuclear magnetic resonance spectroscopy are used to investigate how increases in temperature affect allostery in imidazole glycerol phosphate synthase. Results demonstrate that temperature increase triggers a cascade of local amino acid-to-amino acid dynamics that remarkably resembles the allosteric activation that takes place upon effector binding. The differences in the allosteric response elicited by temperature increase as opposed to effector binding are conditional to the alterations of collective motions induced by either mode of activation. This work provides an atomistic picture of temperature-dependent allostery, which could be harnessed to more precisely control enzyme function.

Allosteric enzyme

Protein Dynamics

10.21203/rs.3.rs-2082238/v1

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Author Correction: Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase

Nature Communications (2023)

Federica Maschietto Uriel N. Morzan Florentina Tofoleanu Aria Gheeraert Apala Chaudhuri

Imidazole

10.1038/s41467-023-38370-3

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Subtle changes at the RBD/hACE2 interface during SARS-CoV2 variant evolution: a molecular dynamics study

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Aria Gheeraert Vincent Leroux Dominique Mias‐Lucquin Yasaman Karami Laurent Vuillon

The SARS-CoV-2 Omicron variants present a different behavior compared to the previous variants, all particularly in respect to the Delta variant, as it seems to promote a lower morbidity although being much more contagious. In this perspective, we performed new molecular dynamics (MD) simulations of the various spike RBD/hACE2 complexes corresponding to the WT, Delta and Omicron variants (BA.1 up to BA.4/5) over 1.5 μs timescale. Then, carrying out a comprehensive analysis of residue interactions within and between the two partners, allowed us to draw the profile of each variant by using complementary methods (PairInt, hydrophobic potential, contact PCA). Main results of PairInt calculations highlighted the most involved residues in electrostatic interactions that represent a strong contribution in the binding with highly stable contacts between spike RBD and hACE2 (importance of mutated residues at positions 417, 493 and 498). In addition to the swappable arginine residues (493/498), the apolar contacts made a substantial and complementary contribution in Omicron with the detection of two hydrophobic patches, one of which was correlated with energetic contribution calculations. This study brings new highlights on the global dynamics of spike RBD/hACE2 complexes resulting from the analysis of contact networks and cross-correlation matrices able to detect subtle changes at point mutations. The results of our study are also consistent with alternative approaches such as binding free energy calculations but are more informative and sensitive to transient or low-energy interactions. Nevertheless, the energetic contributions of residues at positions 501 and 505 were in good agreement with hydrophobic interactions measurements. The contact PCA networks could identify the intramolecular incidence of the S375F mutation occurring in all Omicron variants and likely conferring them an advantage in binding stability. Collectively, these data revealed the major differences observed between WT/Delta and Omicron variants at the RBD/hACE2 interface, which may explain the greater persistence of Omicron.

Dynamics

Interface (matter)

10.1101/2024.12.12.628120

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Elucidating the Activation Mechanism of AMPK by Direct Pan-Activator PF-739

Frontiers in Molecular Biosciences (2021)

Elnaz Aledavood Aria Gheeraert Alessia Forte Laurent Vuillon Ivan Rivalta

Adenosine monophosphate-activated protein kinase (AMPK) is a key energy sensor regulating the cell metabolism in response to energy supply and demand. The evolutionary adaptation of AMPK to different tissues is accomplished through the expression of distinct isoforms that can form up to 12 heterotrimeric complexes, which exhibit notable differences in the sensitivity to direct activators. To comprehend the molecular factors of the activation mechanism of AMPK, we have assessed the changes in the structural and dynamical properties of β1- and β2-containing AMPK complexes formed upon binding to the pan-activator PF-739. The analysis revealed the molecular basis of the PF-739-mediated activation of AMPK and enabled us to identify distinctive features that may justify the slightly higher affinity towards the β1-isoform, such as the β1-Asn111 to β2-Asp111 substitution, which seems to be critical for modulating the dynamical sensitivity of β1- and β2 isoforms. The results are valuable in the design of selective activators to improve the tissue specificity of therapeutic treatment.

AMP-Activated Protein Kinase

10.3389/fmolb.2021.760026

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Connected Component Analysis of Dynamical Perturbation Contact Networks

The Journal of Physical Chemistry B (2023)

Aria Gheeraert Claire Lesieur Víctor S. Batista Laurent Vuillon Ivan Rivalta

Describing protein dynamical networks through amino acid contacts is a powerful way to analyze complex biomolecular systems. However, due to the size of the systems, identifying the relevant features of protein-weighted graphs can be a difficult task. To address this issue, we present the connected component analysis (CCA) approach that allows for fast, robust, and unbiased analysis of dynamical perturbation contact networks (DPCNs). We first illustrate the CCA method as applied to a prototypical allosteric enzyme, the imidazoleglycerol phosphate synthase (IGPS) enzyme from Thermotoga maritima bacteria. This approach was shown to outperform the clustering methods applied to DPCNs, which could not capture the propagation of the allosteric signal within the protein graph. On the other hand, CCA reduced the DPCN size, providing connected components that nicely describe the allosteric propagation of the signal from the effector to the active sites of the protein. By applying the CCA to the IGPS enzyme in different conditions, i.e., at high temperature and from another organism (yeast IGPS), and to a different enzyme, i.e., a protein kinase, we demonstrated how CCA of DPCNs is an effective and transferable tool that facilitates the analysis of protein-weighted networks.

10.1021/acs.jpcb.3c04592

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Exploring Allosteric Pathways of a V-Type Enzyme with Dynamical Perturbation Networks

The Journal of Physical Chemistry B (2019)

Aria Gheeraert Lorenza Pacini Víctor S. Batista Laurent Vuillon Claire Lesieur

Elucidation of the allosteric pathways in proteins is a computational challenge that strongly benefits from combination of atomistic molecular dynamics (MD) simulations and coarse-grained analysis of the complex dynamical network of chemical interactions based on graph theory. Here, we introduce and assess the performances of the dynamical perturbation network analysis of allosteric pathways in a prototypical V-type allosteric enzyme. Dynamical atomic contacts obtained from MD simulations are used to weight the allosteric protein graph, which involves an extended network of contacts perturbed by the effector binding in the allosteric site. The outcome showed good agreement with previously reported theoretical and experimental extended studies and it provided recognition of new potential allosteric spots that can be exploited in future mutagenesis experiments. Overall, the dynamical perturbation network analysis proved to be a powerful computational tool, complementary to other network-based approaches that can assist the full exploitation of allosteric phenomena for advances in protein engineering and rational drug design.

Allosteric enzyme

10.1021/acs.jpcb.9b01294

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Citations (33)

Unraveling the diversity of protein-carbohydrate interfaces: Insights from a multi-scale study

Carbohydrate Research (2025)

Aria Gheeraert Frédéric Guyon Serge Pérez Tatiana Galochkina

10.1016/j.carres.2025.109377

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ATLAS: protein flexibility description from atomistic molecular dynamics simulations

Nucleic Acids Research (2023)

Yann Vander Meersche Gabriel Cretin Aria Gheeraert Jean‐Christophe Gelly Tatiana Galochkina

Abstract Dynamical behaviour is one of the most crucial protein characteristics. Despite the advances in the field of protein structure resolution and prediction, analysis and prediction of protein dynamic properties remains a major challenge, mostly due to the low accessibility of data and its diversity and heterogeneity. To address this issue, we present ATLAS, a database of standardised all-atom molecular dynamics simulations, accompanied by their analysis in the form of interactive diagrams and trajectory visualisation. ATLAS offers a large-scale view and valuable insights on protein dynamics for a large and representative set of proteins, by combining data obtained through molecular dynamics simulations with information extracted from experimental structures. Users can easily analyse dynamic properties of functional protein regions, such as domain limits (hinge positions) and residues involved in interaction with other biological molecules. Additionally, the database enables exploration of proteins with uncommon dynamic properties conditioned by their environment such as chameleon subsequences and Dual Personality Fragments. The ATLAS database is freely available at https://www.dsimb.inserm.fr/ATLAS.

Protein Dynamics

10.1093/nar/gkad1084

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Unraveling the diversity of protein-carbohydrate interfaces: insights from a multi-scale study

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Aria Gheeraert Frédéric Guyon Serge Pérez Tatiana Galochkina

ABSTRACT Protein-carbohydrate interactions play a crucial role in numerous fundamental biological processes. Thus, description and comparison of the carbohydrate binding site (CBS) architecture is of great importance for understanding of the underlying biological mechanisms. However, traditional approaches for carbohydrate-binding protein analysis and annotation rely primarily on the sequence-based methods applied to specific protein classes. The recently released DIONYSUS database aims to fill this gap by providing tools for CBS comparison at different levels: both in terms of protein properties and classification, as well as in terms of atomistic CBS organization. In the current study, we explore DIONYSUS content using a combination of the suggested approaches in order to evaluate the diversity of the currently resolved non-covalent protein-carbohydrate interfaces at different scales. Notably, our analysis reveals evolutionary convergence of CBS in proteins with distinct folds and coming from organisms across different kingdoms of life. Furthermore, we demonstrate that a CBS structure based approach has the potential to facilitate functional annotation for the proteins with missing information in the existing databases. In particular, it provides reliable information for numerous carbohydrate-binding proteins from rapidly evolving organisms, whose analysis is particularly challenging for classical sequence-based methods.

10.1101/2024.10.22.619630

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Singular Interface Dynamics of the SARS-CoV-2 Delta Variant Explained with Contact Perturbation Analysis

Journal of Chemical Information and Modeling (2022)

Aria Gheeraert Laurent Vuillon Laurent Chaloin Olivier Moncorgé Thibaut Véry

Emerging SARS-CoV-2 variants raise concerns about our ability to withstand the Covid-19 pandemic, and therefore, understanding mechanistic differences of those variants is crucial. In this study, we investigate disparities between the SARS-CoV-2 wild type and five variants that emerged in late 2020, focusing on the structure and dynamics of the spike protein interface with the human angiotensin-converting enzyme 2 (ACE2) receptor, by using crystallographic structures and extended analysis of microsecond molecular dynamics simulations. Dihedral angle principal component analysis (PCA) showed the strong similarities in the spike receptor binding domain (RBD) dynamics of the Alpha, Beta, Gamma, and Delta variants, in contrast with those of WT and Epsilon. Dynamical perturbation networks and contact PCA identified the peculiar interface dynamics of the Delta variant, which cannot be directly imputable to its specific L452R and T478K mutations since those residues are not in direct contact with the human ACE2 receptor. Our outcome shows that in the Delta variant the L452R and T478K mutations act synergistically on neighboring residues to provoke drastic changes in the spike/ACE2 interface; thus a singular mechanism of action eventually explains why it dominated over preceding variants.

Dihedral angle

10.1021/acs.jcim.2c00350

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Citations (8)