Protein-Backbone Thermodynamics across the Membrane Interface
Protein-Backbone Thermodynamics across the Membrane Interface
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DOI：
10.1021/acs.jpcb.6b03682
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发表时间：
2016-07-07
影响因子：
3.3
通讯作者：
Kremer, Kurt
中科院分区：
文献类型：
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作者：
Bereau, Tristan;Kremer, Kurt
蛋白质在膜中插入的热力学取决于与脂质环境相互作用的主链和侧链贡献之间的精细相互作用。使用计算机模拟，我们探讨如何不同的描述骨干甘氨酰单位影响热力学插入的个别残基，二肽，和整个跨膜螺旋。由于缺乏参考数据，我们首先介绍了一种有效的方法来估计原子势的平均力（PMF）曲线从一系列的代表性和不相关的粗粒度（CG）快照。我们发现两个CG模型，马提尼和PLUM，对参考原子PMFs和实验之间的强烈差异。原子模拟表明，水和POPC膜之间的甘氨酰单元插入的自由能弱，尽管在我们的计算中有严格的假设，但总体上与实验结果一致。我们表明，精制PLUM中的骨架贡献显著提高了插入WALP 16跨膜肽的PMF。甘氨酰主链和连接的侧链之间的不适当的平衡将导致能量的伪像，合理化马蒂尼的过度稳定的WALP的吸附界面状态。它说明了与基于自由能的单残基模型的参数化相关的困难，因为用于力场参数化的分区的相关自由能不是来自整个残基，而是溶剂可访问的化学基团。
The thermodynamics of insertion of a protein in a membrane depends on the fine interplay between backbone and side-chain contributions interacting with the lipid environment. Using computer simulations, we probe how different descriptions of the backbone glycyl unit affect the thermodynamics of insertion of individual residues, dipeptides, and entire transmembrane helices. Due to the lack of reference data, we first introduce an efficient methodology to estimate atomistic potential of mean force (PMF) curves from a series of representative and uncorrelated coarse-grained (CG) snapshots. We find strong discrepancies between two CG models, Martini and PLUM, against reference atomistic PMFs and experiments. Atomistic simulations suggest a weak free energy of insertion between water and a POPC membrane for the glycyl unit, in overall agreement with experimental results despite severe assumptions in our calculations. We show that refining the backbone contribution in PLUM significantly improves the PMF of insertion of the WALP16 transmembrane peptide. An improper balance between the glycyl backbone and the attached side chain will lead to energetic artifacts, rationalizing Martini's overstabilization of WALP's adsorbed interfacial state. It illustrates difficulties associated with free-energy-based parametrizations of single-residue models, as the relevant free energy of partitioning used for force-field parametrization does not arise from the entire residue but rather the solvent-accessible chemical groups.