Pavlova Anna, Parks Jerry M, Gumbart James C
School of Physics, Georgia Institute of Technology , Atlanta, Georgia 30332, United States.
Biosciences Division, Oak Ridge National Laboratory , Oak Ridge, Tennessee 37831, United States.
J Chem Theory Comput. 2018 Feb 13;14(2):784-798. doi: 10.1021/acs.jctc.7b01236. Epub 2018 Feb 1.
Corrinoid cofactors such as cobalamin are used by many enzymes and are essential for most living organisms. Therefore, there is broad interest in investigating cobalamin-protein interactions with molecular dynamics simulations. Previously developed parameters for cobalamins are based mainly on crystal structure data. Here, we report CHARMM-compatible force field parameters for several corrinoids developed from quantum mechanical calculations. We provide parameters for corrinoids in three oxidation states, Co, Co, and Co, and with various axial ligands. Lennard-Jones parameters for the cobalt center in the Co(II) and Co(I) states were optimized using a helium atom probe, and partial atomic charges were obtained with a combination of natural population analysis (NPA) and restrained electrostatic potential (RESP) fitting approaches. The Force Field Toolkit was used to optimize all bonded terms. The resulting parameters, determined solely from calculations of cobalamin alone or in water, were then validated by assessing their agreement with density functional theory geometries and by analyzing molecular dynamics simulation trajectories of several corrinoid proteins for which X-ray crystal structures are available. In each case, we obtained excellent agreement with the reference data. In comparison to previous CHARMM-compatible parameters for cobalamin, we observe a better agreement for the fold angle and lower RMSD in the cobalamin binding site. The approach described here is readily adaptable for developing CHARMM-compatible force-field parameters for other corrinoids or large biomolecules.
诸如钴胺素之类的类咕啉辅因子被许多酶所使用，并且对大多数生物来说都是必不可少的。因此，利用分子动力学模拟研究钴胺素 - 蛋白质相互作用引起了广泛关注。先前开发的钴胺素参数主要基于晶体结构数据。在此，我们报告了通过量子力学计算得出的几种类咕啉的CHARMM兼容力场参数。我们提供了处于三种氧化态（Co(III)、Co(II)和Co(I)）以及带有各种轴向配体的类咕啉的参数。Co(II)和Co(I)状态下钴中心的 Lennard - Jones参数使用氦原子探针进行了优化，部分原子电荷通过自然布居分析（NPA）和受限静电势（RESP）拟合方法相结合获得。力场工具包用于优化所有键合项。然后，仅通过单独计算钴胺素或在水中计算得出的所得参数，通过评估它们与密度泛函理论几何结构的一致性以及分析几种具有X射线晶体结构的类咕啉蛋白的分子动力学模拟轨迹进行了验证。在每种情况下，我们都与参考数据取得了极好的一致性。与先前的钴胺素CHARMM兼容参数相比，我们观察到在钴胺素结合位点的折叠角方面有更好的一致性并且RMSD更低。这里描述的方法很容易适用于为其他类咕啉或大型生物分子开发CHARMM兼容力场参数。
