Impact of Increased Membrane Realism on Conformational Sampling of Proteins
Impact of Increased Membrane Realism on Conformational Sampling of Proteins
复制标题
增加膜真实性对蛋白质构象采样的影响
DOI：
10.1021/acs.jctc.1c00276
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发表时间：
2021
影响因子：
5.5
通讯作者：
Shukla, Diwakar
中科院分区：
文献类型：
--
作者：
Weigle, Austin T.;Carr, Matthew;Shukla, Diwakar
通过分子动力学 (MD) 进行的脂质双层模拟的真实性和准确性在很大程度上取决于脂质成分。虽然该领域正在推动实现更异质和更真实的膜成分，但缺乏高分辨率的脂质组学数据阻碍了一些膜蛋白系统以最高水平的真实性建模。考虑到现实世界细胞膜和蛋白质-脂质相互作用的额外多样性，目前尚不完全清楚改变膜复杂性如何影响建模的膜蛋白功能，或者它在长时间尺度模拟中是否重要。对于膜环境几乎没有计算研究的生物体来说尤其如此，例如植物质膜。为了同时解决这些问题，本文构建了具有 10 多种不同脂质种类的通用的、现实的和不对称的植物质膜。对纯膜结构进行经典 MD 模拟，以评估改变膜的组成复杂性如何影响植物膜特性。将植物糖转运蛋白 OsSWEET2b 的 Theapoform 插入膜模型中，在该模型中以大小依赖或大小无关的方式计算脂质多样性。进行了由马尔可夫状态模型验证的自适应采样模拟机制，以捕获每个膜结构中 OsSWEET2b 的门控动态。与之前在纯 POPC 双层中进行的 OsSWEET2b 模拟相比，我们确认在类似天然的膜组合物中进行的模拟将 apoOsSWEET2b 构象状态的稳定性改变了约 1 kcal/mol。当实际膜复杂性被简化时，中间构象状态的自由能垒会降低，尽管大致在采样误差范围内，这表明由于成分波动引起的堆积改变，蛋白质对膜的特异性反应有所不同。这项工作作为一个案例研究，其中更真实的双层组成使得无偏构象采样比简化的双层更容易实现。
The realism and accuracy of lipid bilayer simulations through molecular dynamics (MD) are heavily dependent on the lipid composition. While the field is pushing toward implementing more heterogeneous and realistic membrane compositions, a lack of high-resolution lipidomic data prevents some membrane protein systems from being modeled with the highest level of realism. Given the additional diversity of real-world cellular membranes and protein–lipid interactions, it is still not fully understood how altering membrane complexity affects modeled membrane protein functions or if it matters over long-timescale simulations. This is especially true for organisms whose membrane environments have little to no computational study, such as the plant plasma membrane. Tackling these issues in tandem, a generalized, realistic, and asymmetric plant plasma membrane with more than 10 different lipid species is constructed herein. Classical MD simulations of pure membrane constructs were performed to evaluate how altering the compositional complexity of the membrane impacted the plant membrane properties. Theapoform of a plant sugar transporter, OsSWEET2b, was inserted into membrane models where lipid diversity was calculated in either a size-dependent or size-independent manner. An adaptive sampling simulation regime validated by Markov-state models was performed to capture the gating dynamics of OsSWEET2b in each of these membrane constructs. In comparison to previous OsSWEET2b simulations performed in a pure POPC bilayer, we confirm that simulations performed within a native-like membrane composition alter the stabilization ofapoOsSWEET2b conformational states by ∼1 kcal/mol. The free-energy barriers of intermediate conformational states decrease when realistic membrane complexity is simplified, albeit roughly within sampling error, suggesting that protein-specific responses to membranes differ due to altered packing caused by compositional fluctuations. This work serves as a case study where a more realistic bilayer composition makes unbiased conformational sampling easier to achieve than with simplified bilayers.