Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations

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, Co3+, Co2+, and Co1+, 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.钴胺素（cobalamin）等咕啉（corrinoid）辅因子可被众多酶所利用，且对绝大多数生命体至关重要。因此，借助分子动力学模拟研究钴胺素-蛋白质相互作用受到广泛关注。此前报道的钴胺素力场参数主要基于晶体结构数据。本文报道了基于量子力学计算得到的多种咕啉类化合物的兼容CHARMM力场参数。 我们提供了三种氧化态（Co³⁺、Co²⁺和Co¹⁺）且带有多种轴向配体的咕啉类化合物参数。针对Co(II)与Co(I)态下的钴中心，我们采用氦原子探针优化了其伦纳德-琼斯参数，并结合自然布居分析（natural population analysis, NPA）与约束静电势拟合（restrained electrostatic potential, RESP）方法得到了部分原子电荷。我们使用力场工具包（Force Field Toolkit）优化了所有成键项。 上述参数仅通过纯钴胺素或其水溶液的计算得到，随后我们通过两项验证工作对其进行评估：一是与密度泛函理论得到的几何结构进行比对，二是对多种已有X射线晶体结构的咕啉类蛋白质开展分子动力学模拟并分析其轨迹。所有测试均与参考数据实现了高度吻合。 与此前已报道的兼容CHARMM的钴胺素力场参数相比，本参数在折叠角拟合度上表现更优，且在钴胺素结合位点的均方根偏差（RMSD）更低。本文所述方法可轻松推广至其他咕啉类化合物或大型生物分子的兼容CHARMM力场参数开发工作中。