Blanco-González Alexandre, Wurl Anika, Mendes Ferreira Tiago, Piñeiro Ángel, Garcia-Fandino Rebeca
Facultad de Física, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain.
Singular Research Centre in Chemical Biology and Molecular Materials, (CIQUS), Organic Chemistry Department, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain.
J Chem Theory Comput. 2024 Sep 3. doi: 10.1021/acs.jctc.4c00204.
Molecular dynamics (MD) simulations are currently an indispensable tool to understand both the dynamic and nanoscale organization of cell membrane models. A large number of quantitative parameters can be extracted from these simulations, but their reliability is determined by the quality of the employed force field and the simulation parameters. Much of the work on parametrizing and optimizing force fields for biomembrane modeling has been focused on homogeneous bilayers with a single phospholipid type. However, these may not perform effectively or could even be unsuitable for lipid mixtures commonly employed in membrane models. This work aims to fill this gap by comparing MD simulation results of several bacterial membrane models using different force fields and simulation parameters, namely, CHARMM36, Slipids, and GROMOS-CKP. Furthermore, the hydrogen isotope exchange (HIE) method, combined with GROMOS-CKP (GROMOS-H2Q), was also tested to check for the impact of this acceleration strategy on the performance of the force field. A common set of simulation parameters was employed for all of the force fields in addition to those corresponding to the original parametrization of each of them. Furthermore, new experimental order parameter values determined from NMR of several lipid mixtures are also reported to compare them with those determined from MD simulations. Our results reveal that most of the calculated physical properties of bacterial membrane models from MD simulations are substantially force field and lipid composition dependent. Some lipid mixtures exhibit nearly ideal behaviors, while the interaction of different lipid types in other mixtures is highly synergistic. None of the employed force fields seem to be clearly superior to the other three, each having its own strengths and weaknesses. Slipids are notably effective at replicating the order parameters for all acyl chains, including those in lipid mixtures, but they offer the least accurate results for headgroup parameters. Conversely, CHARMM provides almost perfect estimates for the order parameters of the headgroups but tends to overestimate those of the lipid tails. The GROMOS parametrizations deliver reasonable order parameters for entire lipid molecules, including multicomponent bilayers, although they do not reach the accuracy of Slipids for tails or CHARMM for headgroups. Importantly, GROMOS-H2Q stands out for its computational efficiency, being at least 3 times faster than GROMOS, which is already faster than both CHARMM and Slipids. In turn, GROMOS-H2Q yields much higher compressibilities compared to all other parametrizations.
分子动力学（MD）模拟目前是理解细胞膜模型的动态和纳米尺度组织的不可或缺的工具。可以从这些模拟中提取大量定量参数，但其可靠性取决于所采用的力场质量和模拟参数。在为生物膜建模对力场进行参数化和优化方面，许多工作都集中在具有单一磷脂类型的均匀双层膜上。然而，这些力场对于膜模型中常用的脂质混合物可能效果不佳，甚至可能不适用。这项工作旨在通过比较使用不同力场和模拟参数（即CHARMM36、Slipids和GROMOS-CKP）的几种细菌膜模型的MD模拟结果来填补这一空白。此外，还测试了结合GROMOS-CKP（GROMOS-H2Q）的氢同位素交换（HIE）方法，以检查这种加速策略对力场性能的影响。除了与每个力场的原始参数化相对应的参数外，还为所有力场采用了一组通用的模拟参数。此外，还报告了从几种脂质混合物的核磁共振（NMR）测定的新的实验序参数值，以便与从MD模拟确定的值进行比较。我们的结果表明，MD模拟计算得到的细菌膜模型的大多数物理性质在很大程度上取决于力场和脂质组成。一些脂质混合物表现出近乎理想的行为，而其他混合物中不同脂质类型之间的相互作用具有高度协同性。所采用的力场似乎都没有明显优于其他三个，每个都有其自身的优缺点。Slipids在复制所有酰基链（包括脂质混合物中的酰基链）的序参数方面特别有效，但它们对头基团参数的估计最不准确。相反，CHARMM对头基团的序参数提供了几乎完美的估计，但往往高估脂质尾部的序参数。GROMOS参数化方法为整个脂质分子（包括多组分双层膜）提供了合理的序参数，尽管它们在尾部方面没有达到Slipids的精度，在头基团方面也没有达到CHARMM的精度。重要的是，GROMOS-H2Q因其计算效率而脱颖而出，其速度至少比GROMOS快3倍，而GROMOS已经比CHARMM和Slipids都快。相应地，与所有其他参数化方法相比，GROMOS-H2Q产生的压缩率要高得多。
