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Article ; Online: Probing the conformational dynamics of an Ago-RNA complex in water/methanol solution.

Porcelli, Francesco / Casavola, Anna Rita / Grottesi, Alessandro / Schiumarini, Donatella / Avaldi, Lorenzo

Physical chemistry chemical physics : PCCP

2024 Volume 26, Issue 3, Page(s) 2497–2508

Abstract: Argonaute (Ago) proteins mediate target recognition guiding miRNA to bind complementary mRNA primarily in the seed region. However, additional pairing can occur beyond the seed, forming a supplementary duplex that can contribute to the guide-target ... ...

Abstract	Argonaute (Ago) proteins mediate target recognition guiding miRNA to bind complementary mRNA primarily in the seed region. However, additional pairing can occur beyond the seed, forming a supplementary duplex that can contribute to the guide-target affinity. In order to shed light on the connection, between protein-RNA interactions and miRNA-mRNA seed and supplementary duplex mobility, we carried out molecular dynamics simulations at the microsecond time-scale using a different approach compared to the ones normally used. Until now, theoretical investigations with classical MD on Ago-RNA complexes have been focused primarily on pure water solvent, which mimics the natural environment of biological molecules. Here, we explored the conformational space of a human Ago2 (hAgo2) bound to the seed + supplementary miRNA-mRNA duplex, using the solvent environment as a molecular probe. MD simulations have been performed in a mixture of water/MeOH at a molar ratio of 70 : 30 as well as in pure water for comparison. Our findings revealed that the mixed solvent promotes protein RNA association, principally enhancing salt-linkages between basic amino acid side-chains and acidic phosphates of the sugar-phosphate backbone. The primary effect registered was the restriction of supplementary duplex flexibility and the stabilization of the miRNA 3' terminus. Interestingly, we observed that the influence of the solvent appears to have almost no impact on the conformation of the seed duplex.
MeSH term(s)	Humans ; Methanol ; Protein Binding ; MicroRNAs/chemistry ; RNA, Messenger/chemistry ; Solvents
Chemical Substances	Methanol (Y4S76JWI15) ; MicroRNAs ; RNA, Messenger ; Solvents
Language	English
Publishing date	2024-01-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d3cp05530b
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Article ; Online: Pliability in the m

Cazzanelli, Giulia / Dalle Vedove, Andrea / Spagnolli, Giovanni / Terruzzi, Luca / Colasurdo, Enrica / Boldrini, Alberto / Patsilinakos, Alexandros / Sturlese, Mattia / Grottesi, Alessandro / Biasini, Emiliano / Provenzani, Alessandro / Quattrone, Alessandro / Lolli, Graziano

Journal of chemical information and modeling

2024 Volume 64, Issue 5, Page(s) 1682–1690

Abstract: Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the ... ...

Abstract	Epitranscriptomic mRNA modifications affect gene expression, with their altered balance detected in various cancers. YTHDF proteins contain the YTH reader domain recognizing the m
MeSH term(s)	RNA-Binding Proteins/chemistry ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Pliability ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; Molecular Conformation
Chemical Substances	RNA-Binding Proteins ; RNA, Messenger
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.4c00051
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Article ; Online: Phosphorylation, Mg-ADP, and Inhibitors Differentially Shape the Conformational Dynamics of the A-Loop of Aurora-A.

Musavizadeh, Zahra / Grottesi, Alessandro / Guarguaglini, Giulia / Paiardini, Alessandro

Biomolecules

2021 Volume 11, Issue 4

Abstract: The conformational state of the activation loop (A-loop) is pivotal for the activity of most protein kinases. Hence, the characterization of the conformational dynamics of the A-loop is important to increase our understanding of the molecular processes ... ...

Abstract	The conformational state of the activation loop (A-loop) is pivotal for the activity of most protein kinases. Hence, the characterization of the conformational dynamics of the A-loop is important to increase our understanding of the molecular processes related to diseases and to support the discovery of small molecule kinase inhibitors. Here, we carry out a combination of molecular dynamics (MD) and essential dynamics (ED) analyses to fully map the effects of phosphorylation, ADP, and conformation disrupting (CD) inhibitors (i.e., CD532 and MLN8054) on the dynamics of the A-loop of Aurora-A. MD revealed that the stability of the A-loop in an open conformation is enhanced by single phospho-Thr-288, while paradoxically, the presence of a second phosphorylation at Thr-287 decreases such stability and renders the A-loop more fluctuant in time and space. Moreover, we found that this post-translational modification has a significant effect on the direction of the A-loop motions. ED analysis suggests that the presence of the phosphate moiety induces the dynamics of Aurora-A to sample two distinct energy minima, instead of a single large minimum, as in unphosphorylated Aurora-A states. This observation indicates that the conformational distributions of Aurora-A with both single and double phospho-threonine modifications are remarkably different from the unphosphorylated state. In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N- and C-lobes of the kinase domain of Aurora-A, and the angle analysis between those two lobes during MD simulations showed that the N- and C-lobes are kept more open in presence of CD532, compared to MLN8054. As the A-loop is a common feature of Aurora protein kinases, our studies provide a general description of the conformational dynamics of this structure upon phosphorylation and different ligands binding.
MeSH term(s)	Adenosine Diphosphate/chemistry ; Adenosine Diphosphate/metabolism ; Aurora Kinase A/antagonists & inhibitors ; Aurora Kinase A/chemistry ; Aurora Kinase A/metabolism ; Benzazepines/chemistry ; Benzazepines/pharmacology ; Catalytic Domain ; Humans ; Molecular Dynamics Simulation ; Phenylurea Compounds/chemistry ; Phenylurea Compounds/pharmacology ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/pharmacology
Chemical Substances	Benzazepines ; CD532 compound ; MLN8054 ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyrimidines ; Adenosine Diphosphate (61D2G4IYVH) ; Aurora Kinase A (EC 2.7.11.1)
Language	English
Publishing date	2021-04-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11040567
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Article ; Online: Computational Study of Helicase from SARS-CoV-2 in RNA-Free and Engaged Form.

Di Matteo, Francesca / Frumenzio, Giorgia / Chandramouli, Balasubramanian / Grottesi, Alessandro / Emerson, Andrew / Musiani, Francesco

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic that broke out in 2020 and continues to be the cause of massive global upheaval. Coronaviruses are positive-strand RNA viruses with a genome of ~30 kb. ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic that broke out in 2020 and continues to be the cause of massive global upheaval. Coronaviruses are positive-strand RNA viruses with a genome of ~30 kb. The genome is replicated and transcribed by RNA-dependent RNA polymerase together with accessory factors. One of the latter is the protein helicase (NSP13), which is essential for viral replication. The recently solved helicase structure revealed a tertiary structure composed of five domains. Here, we investigated NSP13 from a structural point of view, comparing its RNA-free form with the RNA-engaged form by using atomistic molecular dynamics (MD) simulations at the microsecond timescale. Structural analyses revealed conformational changes that provide insights into the contribution of the different domains, identifying the residues responsible for domain-domain interactions in both observed forms. The RNA-free system appears to be more flexible than the RNA-engaged form. This result underlies the stabilizing role of the nucleic acid and the functional core role of these domains.
Language	English
Publishing date	2022-11-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232314721
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Article ; Online: Conformational response to ligand binding of TMPRSS2, a protease involved in SARS-CoV-2 infection: Insights through computational modeling.

Frumenzio, Giorgia / Chandramouli, Balasubramanian / Besker, Neva / Grottesi, Alessandro / Talarico, Carmine / Frigerio, Francesco / Emerson, Andrew / Musiani, Francesco

Proteins

2023 Volume 91, Issue 9, Page(s) 1288–1297

Abstract: Thanks to the considerable research which has been undertaken in the last few years to improve our understanding of the biology and mechanism of action of SARS-CoV-2, we know how the virus uses its surface spike protein to infect host cells. The ... ...

Abstract	Thanks to the considerable research which has been undertaken in the last few years to improve our understanding of the biology and mechanism of action of SARS-CoV-2, we know how the virus uses its surface spike protein to infect host cells. The transmembrane prosthesis, serine 2 (TMPRSS2) protein, located on the surface of human cells, recognizes the cleavage site in the spike protein, leading to the release of the fusion peptide and entry of the virus into the host cells. Because of its role, TMPRSS2 has been proposed as a drug target to prevent infection by the virus. In this study, we aim to increase our understanding of TMPRSS2 using long scale microsecond atomistic molecular dynamics simulations, focusing on the conformational changes over time. The comparison between simulations conducted on the protein in the native (apo) and inhibited form (holo), has shown that in the holo form the inhibitor stabilizes the catalytic site and induces rearrangements in the extracellular domain of the protein. In turn, it leads to the formation of a new cavity in the vicinity of the ligand binding pocket that is stable in the microsecond time scale. Given the low specificity of known protease inhibitors, these findings suggest a new potential drug target site that can be used to improve TMPRSS2 specific recognition by newly designed inhibitors.
MeSH term(s)	Humans ; COVID-19 ; Peptide Hydrolases/metabolism ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/metabolism ; Ligands ; Molecular Dynamics Simulation ; Virus Internalization ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism
Chemical Substances	Peptide Hydrolases (EC 3.4.-) ; Spike Glycoprotein, Coronavirus ; Ligands ; spike protein, SARS-CoV-2 ; TMPRSS2 protein, human (EC 3.4.21.-) ; Serine Endopeptidases (EC 3.4.21.-)
Language	English
Publishing date	2023-07-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806683-8
ISSN	1097-0134 ; 0887-3585
ISSN (online)	1097-0134
ISSN	0887-3585
DOI	10.1002/prot.26548
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Article: Isoamphipathic antibacterial molecules regulating activity and toxicity through positional isomerism.

Barman, Swagatam / Mukherjee, Sudip / Jolly, Logia / Troiano, Cassandra / Grottesi, Alessandro / Basak, Debajyoti / Calligari, Paolo / Bhattacharjee, Brinta / Bocchinfuso, Gianfranco / Stella, Lorenzo / Haldar, Jayanta

Chemical science

2023 Volume 14, Issue 18, Page(s) 4845–4856

Abstract: Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and ... ...

Abstract	Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. However, optimization of these properties is not enough to circumvent unwanted toxicity towards mammalian cells. Hence, herein, we report new isoamphipathic antibacterial molecules (IAMs:
Language	English
Publishing date	2023-04-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d2sc06065e
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Article ; Online: Thermal compaction of the intrinsically disordered protein tau: entropic, structural, and hydrophobic factors.

Battisti, Anna / Ciasca, Gabriele / Grottesi, Alessandro / Tenenbaum, Alexander

Physical chemistry chemical physics : PCCP

2017 Volume 19, Issue 12, Page(s) 8435–8446

Abstract: Globular denatured proteins have structural properties similar to those of random coils. Experiments on denatured proteins have shown that when the temperature is increased thermal compaction may take place, resulting in a reduction of their radius of ... ...

Abstract	Globular denatured proteins have structural properties similar to those of random coils. Experiments on denatured proteins have shown that when the temperature is increased thermal compaction may take place, resulting in a reduction of their radius of gyration R
Language	English
Publishing date	2017-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/c6cp07683a
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Article ; Online: Revisiting the "satisfaction of spatial restraints" approach of MODELLER for protein homology modeling.

Janson, Giacomo / Grottesi, Alessandro / Pietrosanto, Marco / Ausiello, Gabriele / Guarguaglini, Giulia / Paiardini, Alessandro

PLoS computational biology

2019 Volume 15, Issue 12, Page(s) e1007219

Abstract: The most frequently used approach for protein structure prediction is currently homology modeling. The 3D model building phase of this methodology is critical for obtaining an accurate and biologically useful prediction. The most widely employed tool to ... ...

Abstract	The most frequently used approach for protein structure prediction is currently homology modeling. The 3D model building phase of this methodology is critical for obtaining an accurate and biologically useful prediction. The most widely employed tool to perform this task is MODELLER. This program implements the "modeling by satisfaction of spatial restraints" strategy and its core algorithm has not been altered significantly since the early 1990s. In this work, we have explored the idea of modifying MODELLER with two effective, yet computationally light strategies to improve its 3D modeling performance. Firstly, we have investigated how the level of accuracy in the estimation of structural variability between a target protein and its templates in the form of σ values profoundly influences 3D modeling. We show that the σ values produced by MODELLER are on average weakly correlated to the true level of structural divergence between target-template pairs and that increasing this correlation greatly improves the program's predictions, especially in multiple-template modeling. Secondly, we have inquired into how the incorporation of statistical potential terms (such as the DOPE potential) in the MODELLER's objective function impacts positively 3D modeling quality by providing a small but consistent improvement in metrics such as GDT-HA and lDDT and a large increase in stereochemical quality. Python modules to harness this second strategy are freely available at https://github.com/pymodproject/altmod. In summary, we show that there is a large room for improving MODELLER in terms of 3D modeling quality and we propose strategies that could be pursued in order to further increase its performance.
MeSH term(s)	Algorithms ; Computational Biology ; Models, Molecular ; Molecular Dynamics Simulation/statistics & numerical data ; Proteins/chemistry ; Sequence Alignment/statistics & numerical data ; Software ; Structural Homology, Protein
Chemical Substances	Proteins
Language	English
Publishing date	2019-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1007219
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Article ; Online: Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein.

Borocci, Stefano / Cerchia, Carmen / Grottesi, Alessandro / Sanna, Nico / Prandi, Ingrid Guarnetti / Abid, Nabil / Beccari, Andrea R / Chillemi, Giovanni / Talarico, Carmine

International journal of molecular sciences

2021 Volume 22, Issue 11

Abstract: The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by ... ...

Abstract	The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the "UK variant", in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic "hotspots" and epitopes targeted by neutralizing antibodies.
MeSH term(s)	Antibodies, Neutralizing/immunology ; Binding Sites ; COVID-19/virology ; Epitopes ; Humans ; Hydrogen Bonding ; Molecular Dynamics Simulation ; Polysaccharides/chemistry ; Polysaccharides/metabolism ; Protein Domains ; Protein Interaction Domains and Motifs ; SARS-CoV-2/genetics ; SARS-CoV-2/pathogenicity ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/metabolism ; United Kingdom
Chemical Substances	Antibodies, Neutralizing ; Epitopes ; Polysaccharides ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-05-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22115464
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Article ; Online: Role of the membrane anchor in the regulation of Lck activity.

Porciello, Nicla / Cipria, Deborah / Masi, Giulia / Lanz, Anna-Lisa / Milanetti, Edoardo / Grottesi, Alessandro / Howie, Duncan / Cobbold, Steve P / Schermelleh, Lothar / He, Hai-Tao / D'Abramo, Marco / Destainville, Nicolas / Acuto, Oreste / Nika, Konstantina

The Journal of biological chemistry

2022 Volume 298, Issue 12, Page(s) 102663

Abstract: Theoretical work suggests that collective spatiotemporal behavior of integral membrane proteins should be modulated by boundary lipids sheathing their membrane anchors. Here, we show evidence for this prediction while investigating the mechanism for ... ...

Abstract	Theoretical work suggests that collective spatiotemporal behavior of integral membrane proteins should be modulated by boundary lipids sheathing their membrane anchors. Here, we show evidence for this prediction while investigating the mechanism for maintaining a steady amount of the active form of integral membrane protein Lck kinase (Lck
MeSH term(s)	Leukocyte Common Antigens/metabolism ; Lipid Bilayers/metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Protein Domains
Chemical Substances	Leukocyte Common Antigens (EC 3.1.3.48) ; Lipid Bilayers ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2)
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102663
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