C2 domains facilitate protein interactions with lipid bilayers in either a Ca²⁺-dependent or -independent manner. We used molecular dynamics (MD) simulations to explore six Ca²⁺-independent C2 domains, from KIBRA, PI3KC2α, RIM2, PTEN, SHIP2, and Smurf2. In coarse-grained MD simulations these C2 domains formed transient interactions with zwitterionic bilayers, compared with longer-lived interactions with anionic bilayers containing phosphatidylinositol bisphosphate (PIP₂). Type I C2 domains bound non-canonically via the front, back, or side of the β sandwich, whereas type II C2 domains bound canonically, via the top loops. C2 domains interacted strongly with membranes containing PIP₂, causing bound anionic lipids to cluster around the protein. Binding modes were refined via atomistic simulations. For PTEN and SHIP2, CG simulations of their phosphatase plus C2 domains with PIP₂-containing bilayers were also performed, and the roles of the two domains in membrane localization compared. These studies establish a simulation protocol for membrane-recognition proteins.

^{C2结构域以Ca 2+}依赖性或非依赖性方式促进蛋白质与脂质双层的相互作用。我们使用分子动力学 (MD) 模拟来探索来自 KIBRA、PI3KC2α、RIM2、PTEN、SHIP2 和 Smurf2 的六个 Ca ^{2+独立 C2 结构域。}在粗粒度 MD 模拟中，这些 C2 结构域与两性离子双层形成瞬时相互作用，而与含有磷脂酰肌醇二磷酸 (PIP ₂ ) 的阴离子双层的相互作用寿命更长。I 型 C2 结构域通过 β 夹层的正面、背面或侧面非规范结合，而 II 型 C2 结构域通过顶部环规范结合。_{C2 结构域与含有 PIP 2}的膜强烈相互作用，导致结合的阴离子脂质聚集在蛋白质周围。通过原子模拟改进了结合模式。对于 PTEN 和 SHIP2，还对它们的磷酸酶加 C2 结构域和含有 PIP ₂的双层进行了 CG 模拟，并比较了这两个结构域在膜定位中的作用。这些研究建立了膜识别蛋白的模拟协议。