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Book: Allostery

Di Paola, Luisa / Giuliani, Alessandro

methods and protocols

(Methods in molecular biology ; 2253 ; Springer protocols)

2021

Author's details	edited by Luisa Di Paola, Alessandro Giuliani
Series title	Methods in molecular biology ; 2253 Springer protocols
Collection
Language	English
Size	xii, 274 Seiten, Illustrationen
Publisher	Humana Press
Publishing place	New York, NY
Publishing country	United States
Document type	Book
HBZ-ID	HT020685740
ISBN	978-1-0716-1153-1 ; 9781071611548 ; 1-0716-1153-4 ; 1071611542
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: PyPCN: protein contact networks in PyMOL.

Rosignoli, Serena / di Paola, Luisa / Paiardini, Alessandro

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 11

Abstract: Motivation: Protein contact networks (PCNs) represent the 3D structure of a protein using network formalism. Inter-residue contacts are described as binary adjacency matrices, which are derived from the graph representation of residues (as α-carbons, β- ... ...

Abstract	Motivation: Protein contact networks (PCNs) represent the 3D structure of a protein using network formalism. Inter-residue contacts are described as binary adjacency matrices, which are derived from the graph representation of residues (as α-carbons, β-carbons or centroids) and Euclidean distances according to defined thresholds. Functional characterization algorithms are computed on binary adjacency matrices to unveil allosteric, dynamic, and interaction mechanisms in proteins. Such strategies are usually applied in a combinatorial manner, although rarely in seamless and user-friendly implementations. Results: PyPCN is a plugin for PyMOL wrapping more than twenty PCN algorithms and metrics in an easy-to-use graphical user interface, to support PCN analysis. The plugin accepts 3D structures from the Protein Data Bank, user-provided PDBs, or precomputed adjacency matrices. The results are directly mapped to 3D protein structures and organized into interactive diagrams for their visualization. A dedicated graphical user interface combined with PyMOL visual support makes analysis more intuitive and easier, extending the applicability of PCNs. Availability and implementation: https://github.com/pcnproject/PyPCN.
MeSH term(s)	Proteins/chemistry ; Algorithms ; Software
Chemical Substances	Proteins
Language	English
Publishing date	2023-11-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad675
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Article ; Online: Coevolutionary Analysis and Perturbation-Based Network Modeling of the SARS-CoV-2 Spike Protein Complexes with Antibodies: Binding-Induced Control of Dynamics, Allosteric Interactions and Signaling

Verkhivker, Gennady / Di Paola, Luisa

bioRxiv

Abstract: The structural and biochemical studies of the SARS-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting the link between conformational plasticity of spike proteins and ... ...

Abstract	The structural and biochemical studies of the SARS-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting the link between conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 S complexes with H014, S309, S2M11 and S2E12 antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics, stability and allosteric signaling in the spike protein trimers. The results of this study revealed key regulatory centers that can govern allosteric interactions and communications in the SARS-CoV-2 spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters forming coevolutionary networks. The results revealed significant coevolutionary couplings between functional regions separated by the medium-range distances which may help to facilitate a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. We also discovered a potential mechanism by which antibody-specific targeting of coevolutionary centers can allow for efficient modulation of allosteric interactions and signal propagation between remote functional regions. Using a hierarchical network modeling and perturbation-response scanning analysis, we demonstrated that binding of antibodies could leverage direct contacts with coevolutionary hotspots to allosterically restore and enhance couplings between spatially separated functional regions, thereby protecting the spike apparatus from membrane fusion. The results of this study also suggested that antibody binding can induce a switch from a moderately cooperative population-shift mechanism, governing structural changes of the ligand-free SARS-CoV-2 spike protein, to antibody-induced highly cooperative mechanism that can better withstand mutations in the functional regions without significant deleterious consequences for protein function. This study provides a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 S proteins, showing that antibodies can modulate allosteric interactions and signaling of spike proteins, providing a plausible strategy for therapeutic intervention by targeting specific hotspots of allosteric interactions in the SARS-CoV-2 proteins.
Keywords	covid19
Language	English
Publishing date	2021-01-20
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.01.19.427320
Database	COVID19

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Article ; Online: Computational analysis of the sequence-structure relation in SARS-CoV-2 spike protein using protein contact networks.

Guzzi, Pietro Hiram / di Paola, Luisa / Puccio, Barbara / Lomoio, Ugo / Giuliani, Alessandro / Veltri, Pierangelo

Scientific reports

2023 Volume 13, Issue 1, Page(s) 2837

Abstract: The structure of proteins impacts directly on the function they perform. Mutations in the primary sequence can provoke structural changes with consequent modification of functional properties. SARS-CoV-2 proteins have been extensively studied during the ... ...

Abstract	The structure of proteins impacts directly on the function they perform. Mutations in the primary sequence can provoke structural changes with consequent modification of functional properties. SARS-CoV-2 proteins have been extensively studied during the pandemic. This wide dataset, related to sequence and structure, has enabled joint sequence-structure analysis. In this work, we focus on the SARS-CoV-2 S (Spike) protein and the relations between sequence mutations and structure variations, in order to shed light on the structural changes stemming from the position of mutated amino acid residues in three different SARS-CoV-2 strains. We propose the use of protein contact network (PCN) formalism to: (i) obtain a global metric space and compare various molecular entities, (ii) give a structural explanation of the observed phenotype, and (iii) provide context dependent descriptors of single mutations. PCNs have been used to compare sequence and structure of the Alpha, Delta, and Omicron SARS-CoV-2 variants, and we found that omicron has a unique mutational pattern leading to different structural consequences from mutations of other strains. The non-random distribution of changes in network centrality along the chain has allowed to shed light on the structural (and functional) consequences of mutations.
MeSH term(s)	Humans ; Spike Glycoprotein, Coronavirus ; COVID-19 ; SARS-CoV-2 ; Mutation
Chemical Substances	spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus
Language	English
Publishing date	2023-02-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-30052-w
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Article ; Online: Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches.

Verkhivker, Gennady M / Di Paola, Luisa

The journal of physical chemistry. B

2021 Volume 125, Issue 3, Page(s) 850–873

Abstract: The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable ... ...

Abstract	The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarse-grained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal transmission in the SARS-CoV-2 spike proteins. We found that the experimentally confirmed regulatory hotspots that dictate dynamic switching between conformational states of the SARS-CoV-2 spike protein correspond to the key hinge sites and global mediating centers of the allosteric interaction networks. The results of this study provide a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 spike proteins showing that mutations at the key regulatory positions can differentially modulate distribution of states and determine topography of signal communication pathways operating through state-specific cascades of control switch points. This analysis provides a plausible strategy for allosteric probing of the conformational equilibrium and therapeutic intervention by targeting specific hotspots of allosteric interactions and communications in the SARS-CoV-2 spike proteins.
MeSH term(s)	Allosteric Regulation ; Binding Sites ; Cysteine/genetics ; Models, Biological ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Conformation ; Protein Stability ; Protein Subunits ; SARS-CoV-2/chemistry ; SARS-CoV-2/genetics ; Signal Transduction/genetics ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics
Chemical Substances	Protein Subunits ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Cysteine (K848JZ4886)
Language	English
Publishing date	2021-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.0c10637
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Article ; Online: PCN-Miner: an open-source extensible tool for the analysis of Protein Contact Networks.

Guzzi, Pietro Hiram / Di Paola, Luisa / Giuliani, Alessandro / Veltri, Pierangelo

Bioinformatics (Oxford, England)

2022 Volume 38, Issue 17, Page(s) 4235–4237

Abstract: Motivation: Protein Contact Network (PCN) is a powerful method for analysing the structure and function of proteins, with a specific focus on disclosing the molecular features of allosteric regulation through the discovery of modular substructures. The ... ...

Abstract	Motivation: Protein Contact Network (PCN) is a powerful method for analysing the structure and function of proteins, with a specific focus on disclosing the molecular features of allosteric regulation through the discovery of modular substructures. The importance of PCN analysis has been shown in many contexts, such as the analysis of SARS-CoV-2 Spike protein and its complexes with the Angiotensin Converting Enzyme 2 (ACE2) human receptors. Even if there exist many software tools implementing such methods, there is a growing need for the introduction of tools integrating existing approaches. Results: We present PCN-Miner, a software tool implemented in the Python programming language, able to (i) import protein structures from the Protein Data Bank; (ii) generate the corresponding PCN; (iii) model, analyse and visualize PCNs and related protein structures by using a set of known algorithms and metrics. The PCN-Miner can cover a large set of applications: from clustering to embedding and subsequent analysis. Availability and implementation: The PCN-Miner tool is freely available at the following GitHub repository: https://github.com/hguzzi/ProteinContactNetworks. It is also available in the Python Package Index (PyPI) repository.
MeSH term(s)	Humans ; Programming Languages ; Proteins ; SARS-CoV-2 ; Software ; Protein Interaction Mapping
Chemical Substances	Proteins ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23)
Language	English
Publishing date	2022-07-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btac450
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Article ; Online: Integrated Biophysical Modeling of the SARS-CoV-2 Spike Protein Binding and Allosteric Interactions with Antibodies.

Verkhivker, Gennady M / Di Paola, Luisa

The journal of physical chemistry. B

2021 Volume 125, Issue 18, Page(s) 4596–4619

Abstract: Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity of ... ...

Abstract	Structural and biochemical studies of the severe acute respiratory syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly potent antibodies have revealed multiple conformation-dependent epitopes highlighting conformational plasticity of spike proteins and capacity for eliciting specific binding and broad neutralization responses. In this study, we used coevolutionary analysis, molecular simulations, and perturbation-based hierarchical network modeling of the SARS-CoV-2 spike protein complexes with a panel of antibodies targeting distinct epitopes to explore molecular mechanisms underlying binding-induced modulation of dynamics and allosteric signaling in the spike proteins. Through coevolutionary analysis of the SARS-CoV-2 spike proteins, we identified highly coevolving hotspots and functional clusters that enable a functional cross-talk between distant allosteric regions in the SARS-CoV-2 spike complexes with antibodies. Coarse-grained and all-atom molecular dynamics simulations combined with mutational sensitivity mapping and perturbation-based profiling of the SARS-CoV-2 receptor-binding domain (RBD) complexes with CR3022 and CB6 antibodies enabled a detailed validation of the proposed approach and an extensive quantitative comparison with the experimental structural and deep mutagenesis scanning data. By combining in silico mutational scanning, perturbation-based modeling, and network analysis of the SARS-CoV-2 spike trimer complexes with H014, S309, S2M11, and S2E12 antibodies, we demonstrated that antibodies can incur specific and functionally relevant changes by modulating allosteric propensities and collective dynamics of the SARS-CoV-2 spike proteins. The results provide a novel insight into regulatory mechanisms of SARS-CoV-2 S proteins showing that antibody-escaping mutations can preferentially target structurally adaptable energy hotspots and allosteric effector centers that control functional movements and allosteric communication in the complexes.
MeSH term(s)	COVID-19 ; Humans ; Protein Binding ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.1c00395
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Article ; Online: Network models of biological adaptation at the molecular scale: Comment on "Dynamic and thermodynamic models of adaptation" by A.N. Gorban et al.

Di Paola, Luisa / Leitner, David M

Physics of life reviews

2021 Volume 38, Page(s) 124–126

MeSH term(s)	Acclimatization ; Adaptation, Physiological ; Brain ; Thermodynamics
Language	English
Publishing date	2021-05-28
Publishing country	Netherlands
Document type	Journal Article ; Comment
ZDB-ID	2148883-6
ISSN	1873-1457 ; 1571-0645
ISSN (online)	1873-1457
ISSN	1571-0645
DOI	10.1016/j.plrev.2021.05.008
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Article ; Online: Head or tail? A molecular dynamics approach to the complex structure of TNF-associated factor TRAF2

Erba Fulvio / Di Paola Luisa / Di Venere Almerinda / Mastrangelo Eloise / Cossu Federica / Mei Giampiero / Minicozzi Velia

Biomolecular Concepts, Vol 14, Iss 1, Pp 105-

2023 Volume 53

Abstract: Tumor necrosis factor receptor-associated factor proteins (TRAFs) are trimeric proteins that play a fundamental role in signaling, acting as intermediaries between the tumor necrosis factor (TNF) receptors and the proteins that transmit the downstream ... ...

Abstract	Tumor necrosis factor receptor-associated factor proteins (TRAFs) are trimeric proteins that play a fundamental role in signaling, acting as intermediaries between the tumor necrosis factor (TNF) receptors and the proteins that transmit the downstream signal. The monomeric subunits of all the TRAF family members share a common tridimensional structure: a C-terminal globular domain and a long coiled-coil tail characterizing the N-terminal section. In this study, the dependence of the TRAF2 dynamics on the length of its tail was analyzed in silico. In particular, we used the available crystallographic structure of a C-terminal fragment of TRAF2 (168 out of 501 a.a.), TRAF2-C, and that of a longer construct, addressed as TRAF2-plus, that we have re-constructed using the AlphaFold2 code. The results indicate that the longer N-terminal tail of TRAF2-plus has a strong influence on the dynamics of the globular regions in the protein C-terminal head. In fact, the quaternary interactions among the TRAF2-C subunits change asymmetrically in time, while the movements of TRAF2-plus monomers are rather limited and more ordered than those of the shorter construct. Such findings shed a new light on the dynamics of TRAF subunits and on the protein mechanism in vivo, since TRAF monomer–trimer equilibrium is crucial for several reasons (receptor recognition, membrane binding, hetero-oligomerization).
Keywords	molecular dynamics ; quaternary interaction ; trafs ; protein contact networks ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	De Gruyter
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online: Mapping active allosteric loci SARS-CoV Spike Proteins by means of Protein Contact Networks

Di Paola, Luisa / Giuliani, Alessandro

2020

Abstract: Coronaviruses are a class of virus responsible of the recent outbreak of Human Severe Acute Respiratory Syndrome. The molecular machinery behind the viral entry and thus infectivity is based on the formation of the complex of virus spike protein with the ...

Abstract	Coronaviruses are a class of virus responsible of the recent outbreak of Human Severe Acute Respiratory Syndrome. The molecular machinery behind the viral entry and thus infectivity is based on the formation of the complex of virus spike protein with the angiotensin-converting enzyme 2 (ACE2). The detection of putative allosteric sites on the viral spike protein can trace the path to develop allosteric drugs to weaken the strength of the spike-ACE2 interface and, thus, reduce the viral infectivity. In this work we present results of the application of the Protein Contact Network (PCN) paradigm to the complex SARS-CoV spike - ACE2 relative to both 2003 SARS and the recent 2019 - CoV. Results point to a specific region, present in both structures, that is predicted to act as allosteric site modulating the binding of the spike protein with ACE2. Comment: 13 pages, 2 figures, 2 tables
Keywords	Quantitative Biology - Biomolecules ; Statistics - Applications
Subject code	612
Publishing date	2020-03-11
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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