Department of System Design Engineering, Keio University, Yokohama, Kanagawa 223-8522, Japan.
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Sci Adv. 2020 Feb 19;6(8):eaay5736. doi: 10.1126/sciadv.aay5736. eCollection 2020 Feb.
Association of peripheral proteins with lipid bilayers regulates membrane signaling and dynamics. Pleckstrin homology (PH) domains bind to phosphatidylinositol phosphate (PIP) molecules in membranes. The effects of local PIP enrichment on the interaction of PH domains with membranes is unclear. Molecular dynamics simulations allow estimation of the binding energy of GRP1 PH domain to PIP-containing membranes. The free energy of interaction of the PH domain with more than two PIP molecules is comparable to experimental values, suggesting that PH domain binding involves local clustering of PIP molecules within membranes. We describe a mechanism of PH binding proceeding via an encounter state to two bound states which differ in the orientation of the protein relative to the membrane, these orientations depending on the local PIP concentration. These results suggest that nanoscale clustering of PIP molecules can control the strength and orientation of PH domain interaction in a concentration-dependent manner.
外周蛋白与脂双层的结合调节膜信号转导和动力学。pleckstrin 同源（PH）结构域与膜中的磷脂酰肌醇磷酸（PIP）分子结合。局部 PIP 富集对 PH 结构域与膜相互作用的影响尚不清楚。分子动力学模拟可以估计 GRP1 PH 结构域与含 PIP 膜的结合能。PH 结构域与两个以上 PIP 分子的相互作用自由能与实验值相当，表明 PH 结构域的结合涉及膜内 PIP 分子的局部聚集。我们描述了一种 PH 结合的机制，该机制通过一个遭遇态进行，该遭遇态与两个结合态不同，其区别在于蛋白质相对于膜的取向，这些取向取决于局部 PIP 浓度。这些结果表明，PIP 分子的纳米级聚集可以以浓度依赖的方式控制 PH 结构域相互作用的强度和方向。
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