Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1
Glutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze the nucleophilic addition of the thiol group of reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, which occurs spontaneously but is dramatically...
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MDPI AG
2022-08-01
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| author | Adrien Nicolaï Nicolas Petiot Paul Grassein Patrice Delarue Fabrice Neiers Patrick Senet |
| author_facet | Adrien Nicolaï Nicolas Petiot Paul Grassein Patrice Delarue Fabrice Neiers Patrick Senet |
| author_sort | Adrien Nicolaï |
| collection | DOAJ |
| description | Glutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze the nucleophilic addition of the thiol group of reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, which occurs spontaneously but is dramatically accelerated by the enzyme, protects cells against damages caused by harmful molecules. With some exceptions, GSTs are catalytically active as homodimers, with monomers generally constituted of 200 to 250 residues organized into two subdomains. The first is the N-terminal subdomain, which contains an active site named G site, where GSH is hosted in catalytic conformation and which is generally highly conserved among GSTs. The second subdomain, hydrophobic, which binds the substrate counterpart (H site), can vary from one GST to another, resulting in structures able to recognize different substrates. In the present work, we performed all-atom molecular dynamics simulations in explicit solvent of human GSTA1 in its APO form, bound to GSH ligand and bound to GS-conjugated ligand. From MD, two probes were analyzed to (i) decipher the local conformational changes induced by the presence of the ligand and (ii) map the communication pathways involved in the ligand-binding process. These two local probes are, first, coarse-grained angles <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mo>(</mo><mi>θ</mi></mrow></semantics></math></inline-formula>,<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>γ</mi><mo>)</mo></mrow></semantics></math></inline-formula>, representing the local conformation of the protein main chain and, second, dihedral angles <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>χ</mi></semantics></math></inline-formula> representing the local conformation of the amino-acid side chains. From the local probes time series, effective free-energy landscapes along the amino-acid sequence were analyzed and compared between the three different forms of GSTA1. This methodology allowed us to extract a network of 33 key residues, some of them being located in the experimentally well-known binding sites G and H of GSTA1 and others being located as far as 30Å from the original binding sites. Finally, the collective motions associated with the network of key residues were established, showing a strong dynamical coupling between residues Gly14-Arg15 and Gln54-Val55, both in the same binding site (intrasite) but also between binding sites of each monomer (intersites). |
| first_indexed | 2024-03-09T04:43:34Z |
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| spelling | doaj.art-052ba3f141164e8b97640b6b954a33212023-12-03T13:17:50ZengMDPI AGApplied Sciences2076-34172022-08-011216819610.3390/app12168196Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1Adrien Nicolaï0Nicolas Petiot1Paul Grassein2Patrice Delarue3Fabrice Neiers4Patrick Senet5Laboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, FranceLaboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, FranceLaboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, FranceLaboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, FranceCentre des Sciences du Goût et de l’Alimentation (CSGA), Université de Bourgogne Franche-Comté, INRA, CNRS, 21000 Dijon, FranceLaboratoire Interdisciplinaire Carnot de Bourgogne, UMR 6303 CNRS-Université de Bourgogne Franche-Comté, 21078 Dijon, FranceGlutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze the nucleophilic addition of the thiol group of reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, which occurs spontaneously but is dramatically accelerated by the enzyme, protects cells against damages caused by harmful molecules. With some exceptions, GSTs are catalytically active as homodimers, with monomers generally constituted of 200 to 250 residues organized into two subdomains. The first is the N-terminal subdomain, which contains an active site named G site, where GSH is hosted in catalytic conformation and which is generally highly conserved among GSTs. The second subdomain, hydrophobic, which binds the substrate counterpart (H site), can vary from one GST to another, resulting in structures able to recognize different substrates. In the present work, we performed all-atom molecular dynamics simulations in explicit solvent of human GSTA1 in its APO form, bound to GSH ligand and bound to GS-conjugated ligand. From MD, two probes were analyzed to (i) decipher the local conformational changes induced by the presence of the ligand and (ii) map the communication pathways involved in the ligand-binding process. These two local probes are, first, coarse-grained angles <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mo>(</mo><mi>θ</mi></mrow></semantics></math></inline-formula>,<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>γ</mi><mo>)</mo></mrow></semantics></math></inline-formula>, representing the local conformation of the protein main chain and, second, dihedral angles <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi>χ</mi></semantics></math></inline-formula> representing the local conformation of the amino-acid side chains. From the local probes time series, effective free-energy landscapes along the amino-acid sequence were analyzed and compared between the three different forms of GSTA1. This methodology allowed us to extract a network of 33 key residues, some of them being located in the experimentally well-known binding sites G and H of GSTA1 and others being located as far as 30Å from the original binding sites. Finally, the collective motions associated with the network of key residues were established, showing a strong dynamical coupling between residues Gly14-Arg15 and Gln54-Val55, both in the same binding site (intrasite) but also between binding sites of each monomer (intersites).https://www.mdpi.com/2076-3417/12/16/8196enzymeligand bindingmolecular dynamicsfree-energycoarse-grained angles |
| spellingShingle | Adrien Nicolaï Nicolas Petiot Paul Grassein Patrice Delarue Fabrice Neiers Patrick Senet Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 Applied Sciences enzyme ligand binding molecular dynamics free-energy coarse-grained angles |
| title | Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 |
| title_full | Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 |
| title_fullStr | Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 |
| title_full_unstemmed | Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 |
| title_short | Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1 |
| title_sort | free energy landscape analysis of protein ligand binding the case of human glutathione transferase a1 |
| topic | enzyme ligand binding molecular dynamics free-energy coarse-grained angles |
| url | https://www.mdpi.com/2076-3417/12/16/8196 |
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