Fly-Casting with Ligand–Sliding and Orientational Selection to Support the Complex Formation of a GPCR and a Middle-Sized Flexible Molecule
Abstract A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was performed to elucidate a binding mechanism of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is one of generalized ensemble methods and produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stably keeping the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model, and sampling was carried out from conformations where bosentan was distant from the binding site in the hETB’s binding pocket. The deepest basin in the resultant free-energy landscape was assigned to the native-like complex conformation. The obtained binding mechanism is as follows. First, bosentan fluctuating randomly in solution is captured by a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly-casting). Bosentan then occasionally slides from the tip to root of the N-terminal tail (ligand–sliding). In this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with accompanying a quick reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed, and eventually the native-like complex is completed. The bosentan-captured conformations by the tip- and root-regions of the N-terminal tail correspond to two basins in the free-energy landscape, and the ligand–sliding corresponds to overcoming a free-energy barrier between the basins..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
ResearchSquare.com - (2022) vom: 09. März Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Higo, Junichi [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-1415525/v1 |
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XRA035440945 |
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| 520 | |a Abstract A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was performed to elucidate a binding mechanism of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is one of generalized ensemble methods and produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stably keeping the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model, and sampling was carried out from conformations where bosentan was distant from the binding site in the hETB’s binding pocket. The deepest basin in the resultant free-energy landscape was assigned to the native-like complex conformation. The obtained binding mechanism is as follows. First, bosentan fluctuating randomly in solution is captured by a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly-casting). Bosentan then occasionally slides from the tip to root of the N-terminal tail (ligand–sliding). In this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with accompanying a quick reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed, and eventually the native-like complex is completed. The bosentan-captured conformations by the tip- and root-regions of the N-terminal tail correspond to two basins in the free-energy landscape, and the ligand–sliding corresponds to overcoming a free-energy barrier between the basins. | ||
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| 700 | 1 | |a Bekker, Gert-Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Benson |e verfasserin |4 aut | |
| 700 | 1 | |a Sakuraba, Shun |e verfasserin |4 aut | |
| 700 | 1 | |a Iida, Shinji |e verfasserin |4 aut | |
| 700 | 1 | |a Kamiya, Narutoshi |e verfasserin |4 aut | |
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| 700 | 1 | |a Kono, Hidetoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Fukunishi, Yoshifumi |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Haruki |e verfasserin |4 aut | |
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