Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields
Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields
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绒毛头件蛋白的可溶态作为 MD 力场评估的工具
DOI：
10.1021/acs.jpcb.1c04589
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Urbanc, Brigita
中科院分区：
文献类型：
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作者：
Andrews, Brian;Long, Kaho;Urbanc, Brigita
蛋白质自组装在细胞过程中起着重要的作用。虽然分子动力学(MD)是研究组装机制的一个强大工具，但它的预测依赖于潜在力场的准确性，众所周知，力场过度促进蛋白质组装。我们在这里研究维林头盔结构域，HP36，它在符合MD研究的浓度下仍然是可溶的。对浓度为0.05-1 mM的可溶性HP36的实验表征表明，90%的单体和10%的二聚体与浓度无关。在两种蛋白质浓度(0.9和8.5 mM)下进行广泛的全原子MD模拟，探索HP36二聚体在两个MD力场Amber ff14SB和CHARMM36m中的数量、稳定性和形成动力学。MD结果表明，虽然CHARMM36M在低浓度时捕获了实验的HP36单体种群，但在较高浓度时，两种力场都过度促进了HP36的缔合。此外，稳定HP36二聚体的接触是依赖于力场的。与琥珀ff14SB相比，CHARMM36m产生持续较高的HP36单体种群，较低的缔合率，以及这些数量对蛋白质浓度的较弱依赖。然而，当琥珀FF14SB中的TIP3P水模型被TIP4P/2005取代时，观察到最高的单体数量和解离常数，这表明水模型在解决MD中的蛋白质溶解性问题方面发挥了关键作用。
Protein self-assembly plays an important role in cellular processes. Whereas molecular dynamics (MD) represents a powerful tool in studying assembly mechanisms, its predictions depend on the accuracy of underlying force fields, which are known to overly promote protein assembly. We here examine villin headpiece domain, HP36, which remains soluble at concentrations amenable to MD studies. The experimental characterization of soluble HP36 at concentrations of 0.05 to 1 mM reveals concentration-independent 90% monomeric and 10% dimeric populations. Extensive all-atom MD simulations at two protein concentrations, 0.9 and 8.5 mM, probe the HP36 dimer population, stability, and kinetics of dimer formation within two MD force fields, Amber ff14SB and CHARMM36m. MD results demonstrate that whereas CHARMM36m captures experimental HP36 monomer populations at the lower concentration, both force fields overly promote HP36 association at the higher concentration. Moreover, contacts stabilizing HP36 dimers are force-field-dependent. CHARMM36m produces consistently higher HP36 monomer populations, lower association rates, and weaker dependence of these quantities on the protein concentration than Amber ff14SB. Nonetheless, the highest monomer populations and dissociation constants are observed when the TIP3P water model in Amber ff14SB is replaced by TIP4P/2005, showcasing the critical role of the water model in addressing the protein solubility problem in MD.