Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model.
Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived con...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-04-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC3974643?pdf=render |
| _version_ | 1811226855019118592 |
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| author | Avisek Das Mert Gur Mary Hongying Cheng Sunhwan Jo Ivet Bahar Benoît Roux |
| author_facet | Avisek Das Mert Gur Mary Hongying Cheng Sunhwan Jo Ivet Bahar Benoît Roux |
| author_sort | Avisek Das |
| collection | DOAJ |
| description | Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results. |
| first_indexed | 2024-04-12T09:31:47Z |
| format | Article |
| id | doaj.art-de61a480973d47b6b6dacbc952c389f6 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T09:31:47Z |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-de61a480973d47b6b6dacbc952c389f62022-12-22T03:38:20ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582014-04-01104e100352110.1371/journal.pcbi.1003521Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model.Avisek DasMert GurMary Hongying ChengSunhwan JoIvet BaharBenoît RouxBiomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results.http://europepmc.org/articles/PMC3974643?pdf=render |
| spellingShingle | Avisek Das Mert Gur Mary Hongying Cheng Sunhwan Jo Ivet Bahar Benoît Roux Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. PLoS Computational Biology |
| title | Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. |
| title_full | Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. |
| title_fullStr | Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. |
| title_full_unstemmed | Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. |
| title_short | Exploring the conformational transitions of biomolecular systems using a simple two-state anisotropic network model. |
| title_sort | exploring the conformational transitions of biomolecular systems using a simple two state anisotropic network model |
| url | http://europepmc.org/articles/PMC3974643?pdf=render |
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