A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms
Protein homodimers have been classified as three-state or two-state dimers depending on whether a folded monomer forms before association, but the details of the folding–binding mechanisms are poorly understood. Kinetic transition networks of conformational states have provided insight into the fold...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/12/1708 |
| _version_ | 1797381893918818304 |
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| author | Dániel Györffy Péter Závodszky András Szilágyi |
| author_facet | Dániel Györffy Péter Závodszky András Szilágyi |
| author_sort | Dániel Györffy |
| collection | DOAJ |
| description | Protein homodimers have been classified as three-state or two-state dimers depending on whether a folded monomer forms before association, but the details of the folding–binding mechanisms are poorly understood. Kinetic transition networks of conformational states have provided insight into the folding mechanisms of monomeric proteins, but extending such a network to two protein chains is challenging as all the relative positions and orientations of the chains need to be included, greatly increasing the number of degrees of freedom. Here, we present a simplification of the problem by grouping all states of the two chains into two layers: a dissociated and an associated layer. We combined our two-layer approach with the Wako–Saito–Muñoz–Eaton method and used Transition Path Theory to investigate the dimer formation kinetics of eight homodimers. The analysis reveals a remarkable diversity of dimer formation mechanisms. Induced folding, conformational selection, and rigid docking are often simultaneously at work, and their contribution depends on the protein concentration. Pre-folded structural elements are always present at the moment of association, and asymmetric binding mechanisms are common. Our two-layer network approach can be combined with various methods that generate discrete states, yielding new insights into the kinetics and pathways of flexible binding processes. |
| first_indexed | 2024-03-08T20:58:04Z |
| format | Article |
| id | doaj.art-ca2981c079034ebcbe38caeaa9ab6332 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-08T20:58:04Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-ca2981c079034ebcbe38caeaa9ab63322023-12-22T13:55:51ZengMDPI AGBiomolecules2218-273X2023-11-011312170810.3390/biom13121708A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation MechanismsDániel Györffy0Péter Závodszky1András Szilágyi2Systems Biology of Reproduction Research Group, Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, HungaryStructural Biophysics Research Group, Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, HungarySystems Biology of Reproduction Research Group, Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, HungaryProtein homodimers have been classified as three-state or two-state dimers depending on whether a folded monomer forms before association, but the details of the folding–binding mechanisms are poorly understood. Kinetic transition networks of conformational states have provided insight into the folding mechanisms of monomeric proteins, but extending such a network to two protein chains is challenging as all the relative positions and orientations of the chains need to be included, greatly increasing the number of degrees of freedom. Here, we present a simplification of the problem by grouping all states of the two chains into two layers: a dissociated and an associated layer. We combined our two-layer approach with the Wako–Saito–Muñoz–Eaton method and used Transition Path Theory to investigate the dimer formation kinetics of eight homodimers. The analysis reveals a remarkable diversity of dimer formation mechanisms. Induced folding, conformational selection, and rigid docking are often simultaneously at work, and their contribution depends on the protein concentration. Pre-folded structural elements are always present at the moment of association, and asymmetric binding mechanisms are common. Our two-layer network approach can be combined with various methods that generate discrete states, yielding new insights into the kinetics and pathways of flexible binding processes.https://www.mdpi.com/2218-273X/13/12/1708protein foldingprotein bindingkinetic networkhomodimerconformational selectioninduced fit |
| spellingShingle | Dániel Györffy Péter Závodszky András Szilágyi A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms Biomolecules protein folding protein binding kinetic network homodimer conformational selection induced fit |
| title | A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms |
| title_full | A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms |
| title_fullStr | A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms |
| title_full_unstemmed | A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms |
| title_short | A Kinetic Transition Network Model Reveals the Diversity of Protein Dimer Formation Mechanisms |
| title_sort | kinetic transition network model reveals the diversity of protein dimer formation mechanisms |
| topic | protein folding protein binding kinetic network homodimer conformational selection induced fit |
| url | https://www.mdpi.com/2218-273X/13/12/1708 |
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