Stanley Nathaniel, Pardo Leonardo, Fabritiis Gianni De
Computational Biophysics Laboratory (GRIB-IMIM), Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), C/Doctor Aiguader 88, 08003 Barcelona, Spain.
Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Sci Rep. 2016 Mar 4;6:22639. doi: 10.1038/srep22639.
The binding process through the membrane bilayer of lipid-like ligands to a protein target is an important but poorly explored recognition process at the atomic level. In this work we succeeded in resolving the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a "membrane vestibule" at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the "membrane vestibule" is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies.
类脂配体通过膜双层与蛋白质靶点的结合过程是一个重要但在原子水平上探索较少的识别过程。在这项工作中，我们通过超过800微秒的聚集采样无偏分子动力学模拟，成功解析了脂质抑制剂ML056与1-磷酸鞘氨醇受体1（S1P1R）的结合。结合途径是一个多阶段过程，包括配体在双层小叶中扩散以接触跨膜区7顶部的“膜前庭”，随后从这个面向脂质的前庭通过由跨膜区1和7以及受体的N端形成的通道移动到正构结合腔。配体进入时，N端α-螺旋的展开增加了通道的体积，有助于达到晶体学构象，该构象也对应于预测的有利构象。结合过程的弛豫时间尺度表明，配体与“膜前庭”的结合是多微秒时间尺度上的限速步骤。我们在其他结合研究的背景下评论了结合过程的意义和相似之处。
