Liao Chenyi, Zhao Xiaochuan, Liu Jiyuan, Schneebeli Severin T, Shelley John C, Li Jianing
Department of Chemistry, The University of Vermont, Burlington, VT 05405, USA.
Schrödinger, Inc., 101 SW Main Street, Suite 1300, Portland, OR 97204, USA.
Phys Chem Chem Phys. 2017 Mar 29;19(13):9181-9188. doi: 10.1039/c7cp00200a.
The structures and dynamics of protein complexes are often challenging to model in heterogeneous environments such as biological membranes. Herein, we meet this fundamental challenge at attainable cost with all-atom, mixed-resolution, and coarse-grained models of vital membrane proteins. We systematically simulated five complex models formed by two distinct G protein-coupled receptors (GPCRs) in the lipid-bilayer membrane on the ns-to-μs timescales. These models, which suggest the swinging motion of an intracellular loop, for the first time, provide the molecular details for the regulatory role of such a loop. For the models at different resolutions, we observed consistent structural stability but various levels of speed-ups in protein dynamics. The mixed-resolution and coarse-grained models show two and four times faster protein diffusion than the all-atom models, in addition to a 4- and 400-fold speed-up in the simulation performance. Furthermore, by elucidating the strengths and challenges of combining all-atom models with reduced resolution models, this study can serve as a guide to simulating other complex systems in heterogeneous environments efficiently.
在诸如生物膜这样的异质环境中，蛋白质复合物的结构和动力学通常很难建模。在此，我们用重要膜蛋白的全原子、混合分辨率和粗粒度模型，以可承受的成本应对这一根本挑战。我们在纳秒到微秒的时间尺度上，系统地模拟了由两种不同的G蛋白偶联受体（GPCR）在脂质双分子层膜中形成的五种复合物模型。这些模型表明细胞内环存在摆动运动，首次提供了该环调节作用的分子细节。对于不同分辨率的模型，我们观察到结构稳定性一致，但蛋白质动力学的加速程度不同。混合分辨率和粗粒度模型显示蛋白质扩散速度比全原子模型快两倍和四倍，此外模拟性能还分别提高了4倍和400倍。此外，通过阐明将全原子模型与低分辨率模型相结合的优势和挑战，本研究可为高效模拟异质环境中的其他复杂系统提供指导。
