Addressing the Excessive Aggregation of Membrane Proteins in the MARTINI Model.
Addressing the Excessive Aggregation of Membrane Proteins in the MARTINI Model.
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DOI：
10.1021/acs.jctc.0c01253
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发表时间：
2021-04-13
影响因子：
5.5
通讯作者：
Straub JE
中科院分区：
文献类型：
--
作者：
Majumder A;Straub JE
MARTINI模型是一种广泛使用的粗粒度力场，因其能够代表多种复杂生物分子而广受欢迎。然而，模拟越来越逼真的膜模型，包括复杂的脂质混合物和多种蛋白质，表明膜蛋白聚集体被MARTINI v2.2力场过度稳定。在本研究中，我们解决了MARTINI模型的这一缺点。我们用非极化MARTINI模型测定了四种跨膜蛋白体系二聚化的自由能。与实验中基于fret的二聚化自由能的估计进行比较，以量化所研究的每种蛋白质同型二聚体的显着过稳定化。为了提高模拟与实验的一致性，采用单一的均匀比例因子α来增强蛋白-脂质Lennard-Jones相互作用。发现α = 1.04-1.045最适合于所研究的蛋白质的二聚化自由能，同时保持二聚体界面接触的特异性。为了进一步验证修改后的力场，我们使用MARTINI v2.2和重新参数化的MARTINI模型进行了多蛋白模拟。最初的MARTINI模型预测了蛋白质的寡聚化成单个聚集体，而重新参数化的MARTINI模型维持了实验研究预测的单体和二聚体之间的动态平衡。提出的重新参数化是标准MARTINI模型的替代方案，用于模拟含有多种脂质和蛋白质的生物膜的现实模型。
The MARTINI model is a widely used coarse-grained force field popular for its capacity to represent a diverse array of complex biomolecules. However, efforts to simulate increasingly realistic models of membranes, involving complex lipid mixtures and multiple proteins, suggest that membrane protein aggregates are overstabilized by the MARTINI v2.2 force field. In this study, we address this shortcoming of the MARTINI model. We determined the free energy of dimerization of four transmembrane protein systems using the nonpolarizable MARTINI model. Comparison with experimental FRET-based estimates of the dimerization free energy was used to quantify the significant overstabilization of each protein homodimer studied. To improve the agreement between simulation and experiment, a single uniform scaling factor, α, was used to enhance the protein–lipid Lennard–Jones interaction. A value of α = 1.04–1.045 was found to provide the best fit to the dimerization free energies for the proteins studied while maintaining the specificity of contacts at the dimer interface. To further validate the modified force field, we performed a multiprotein simulation using both MARTINI v2.2 and the reparameterized MARTINI model. While the original MARTINI model predicts oligomerization of protein into a single aggregate, the reparameterized MARTINI model maintains a dynamic equilibrium between monomers and dimers as predicted by experimental studies. The proposed reparameterization is an alternative to the standard MARTINI model for use in simulations of realistic models of a biological membrane containing diverse lipids and proteins.
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