Derivation of Fixed Partial Charges for Amino Acids Accommodating a Specific Water Model and Implicit Polarization

We have developed the IPolQ method for fitting nonpolarizable point charges to implicitly represent the energy of polarization for systems in pure water. The method involves iterative cycles of molecular dynamics simulations to estimate the water charge density around the solute of interest, followed by quantum mechanical calculations at the MP2/cc-pV­(T+d)­Z level to determine updated solute charges. Lennard-Jones parameters are updated starting from the Amber FF99SB nonbonded parameter set to accommodate the new charge model, guided by the comparisons to experimental hydration free energies (HFEs) of neutral amino acid side chain analogs and assumptions about the computed HFEs for charged side chains. These Lennard-Jones parameter adjustments for side-chain analogs are assumed to be transferable to amino acids generally, and new charges for all standard amino acids are then derived in the presence of water modeled by TIP4P-Ew. Overall, the new charges depict substantially more polarized amino acids, particularly in the backbone moieties, than previous Amber charge sets. Efforts to complete a new force field with appropriate torsion parameters for this charge model are underway. The IPolQ method is general and applicable to arbitrary solutes.我们开发了IPolQ方法，用于拟合不可极化点电荷，以隐式表征纯水环境中目标溶质的极化能。该方法包含多轮迭代的分子动力学模拟，以估算目标溶质周围的水分子电荷密度；随后在MP2/cc-pV(T+d)Z级别下开展量子力学计算，以更新溶质电荷参数。我们以Amber FF99SB非键相互作用参数集为基础更新伦纳德-琼斯参数（Lennard-Jones parameters），以适配新的电荷模型；校准依据为中性氨基酸侧链类似物的实验溶剂化自由能（hydration free energies, HFE）比对结果，以及带电侧链的计算溶剂化自由能假设。上述针对侧链类似物的伦纳德-琼斯参数调整被假定可推广至所有氨基酸；随后在TIP4P-Ew水分子模型的水环境中，推导得到所有标准氨基酸的全新电荷参数。总体而言，相较于此前的Amber电荷参数集，新电荷参数能更显著地表征氨基酸的极化程度，尤其是在主链片段中。目前，我们正致力于为该电荷模型配套合适的二面角参数以构建完整的新型力场。IPolQ方法具有普适性，可应用于任意溶质体系。