Fly casting with ligand sliding and orientational selection supporting complex formation of a GPCR and a middle sized flexible molecule.
Fly casting with ligand sliding and orientational selection supporting complex formation of a GPCR and a middle sized flexible molecule.
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DOI：
10.1038/s41598-022-17920-7
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发表时间：
2022-08-13
影响因子：
4.6
通讯作者：
Nakamura, Haruki
中科院分区：
文献类型：
--
作者：
Higo, Junichi;Kasahara, Kota;Bekker, Gert-Jan;Ma, Benson;Sakuraba, Shun;Iida, Shinji;Kamiya, Narutoshi;Fukuda, Ikuo;Kono, Hidetoshi;Fukunishi, Yoshifumi;Nakamura, Haruki
采用GA引导的多维虚拟系统耦合分子动力学（GA-mD-VcMD）模拟方法，研究了中等大小的柔性分子波生坦与GPCR蛋白--人内皮素受体B（hET B）的结合机制。GA-mD-VcMD是一种广义的集成方法，通过搜索伴随着稳定维持脆弱的细胞膜结构的大规模运动来产生配体-受体结合的自由能景观。所有分子组分（波生坦、hETB、膜和溶剂）均采用全原子模型表示。然后从波生坦远离hETB结合口袋中结合位点的构象进行取样。在由此产生的自由能景观最深的盆地被分配到本地样复杂的构象。推断出以下结合机制。首先，使用hETB的柔性N-末端尾部的尖端区域通过非特异性吸引相互作用（蝇投）捕获溶液中随机波动的波生坦。然后波生坦偶尔从N-末端尾部的尖端滑动到根部（配体滑动）。在该滑动过程中，波生坦从袋外到袋内通过结合袋的门，伴随波生坦分子取向多样性的快速减少（取向选择）。最后，在口袋中，配体-受体吸引的天然接触形成。最终，这一本土化的综合体完成了。波生坦捕获的构象的尖端区域和根区域的N-末端尾巴对应于两个盆地中的自由能景观。配体滑动对应于克服盆地之间的自由能势垒。
A GA-guided multidimensional virtual-system coupled molecular dynamics (GA-mD-VcMD) simulation was conducted to elucidate binding mechanisms of a middle-sized flexible molecule, bosentan, to a GPCR protein, human endothelin receptor type B (hETB). GA-mD-VcMD is a generalized ensemble method that produces a free-energy landscape of the ligand-receptor binding by searching large-scale motions accompanied with stable maintenance of the fragile cell-membrane structure. All molecular components (bosentan, hETB, membrane, and solvent) were represented with an all-atom model. Then sampling was conducted from conformations where bosentan was distant from the binding site in the hETB binding pocket. The deepest basin in the resultant free-energy landscape was assigned to native-like complex conformation. The following binding mechanism was inferred. First, bosentan fluctuating randomly in solution is captured using a tip region of the flexible N-terminal tail of hETB via nonspecific attractive interactions (fly casting). Bosentan then slides occasionally from the tip to the root of the N-terminal tail (ligand–sliding). During this sliding, bosentan passes the gate of the binding pocket from outside to inside of the pocket with an accompanying rapid reduction of the molecular orientational variety of bosentan (orientational selection). Last, in the pocket, ligand–receptor attractive native contacts are formed. Eventually, the native-like complex is completed. The bosentan-captured conformations by the tip-region and root-region of the N-terminal tail correspond to two basins in the free-energy landscape. The ligand-sliding corresponds to overcoming of a free-energy barrier between the basins.
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影响因子：
16.6
作者：
Che, Tao;English, Justin;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
2.9
作者：
HOOVER, WG
通讯作者：
HOOVER, WG
影响因子：
14.8
作者：
Ersoy, Baran A.;Pardo, Leonardo;Zhang, Sumei;Thompson, Darren A.;Millhauser, Glenn;Govaerts, Cedric;Vaisse, Christian
通讯作者：
Vaisse, Christian
影响因子：
4.4
作者：
Fukuda, Ikuo;Yonezawa, Yasushige;Nakamura, Haruki
通讯作者：
Nakamura, Haruki
影响因子：
3
作者：
Ikebe, Jinzen;Umezawa, Koji;Higo, Junichi
通讯作者：
Higo, Junichi