Guvench Olgun, Hatcher Elizabeth R, Venable Richard M, Pastor Richard W, Mackerell Alexander D
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street HSF II, Baltimore MD 21201.
J Chem Theory Comput. 2009 Aug 20;5(9):2353-2370. doi: 10.1021/ct900242e.
We present an extension of the CHARMM hexopyranose monosaccharide additive all-atom force field to enable modeling of glycosidic-linked hexopyranose polysaccharides. The new force field parameters encompass 1→1, 1→2, 1→3, 1→4, and 1→6 hexopyranose glycosidic linkages, as well as O-methylation at the C(1) anomeric carbon, and are developed to be consistent with the CHARMM all-atom biomolecular force fields for proteins, nucleic acids, and lipids. The parameters are developed in a hierarchical fashion using model compounds containing the key atoms in the full carbohydrates, in particular O-methyl-tetrahydropyran and glycosidic-linked dimers consisting of two molecules of tetrahyropyran or one of tetrahydropyran and one of cyclohexane. Target data for parameter optimization include full two-dimensional energy surfaces defined by the Φ/Ψ glycosidic dihedral angles in the disaccharide analogs as determined by quantum mechanical MP2/cc-pVTZ single point energies on MP2/6-31G(d) optimized structures (MP2/cc-pVTZ//MP2/6-31G(d)). In order to achieve balanced, transferable dihedral parameters for the Φ/Ψ glycosidic dihedral angles, surfaces for all possible chiralities at the ring carbon atoms involved in the glycosidic linkages are considered, resulting in over 5000 MP2/cc-pVTZ//MP2/6-31G(d) conformational energies. Also included as target data are vibrational frequencies, pair interaction energies and distances with water molecules, and intramolecular geometries including distortion of the glycosidic valence angle as a function of the glycosidic dihedral angles. The model-compound optimized force field parameters are validated on full disaccharides through comparison of molecular dynamics results to available experimental data. Good agreement is achieved with experiment for a variety of properties including crystal cell parameters and intramolecular geometries, aqueous densities, and aqueous NMR coupling constants associated with the glycosidic linkage. The newly-developed parameters allow for the modeling of linear, branched, and cyclic hexopyranose glycosides both alone and in heterogenous systems including proteins, nucleic acids and/or lipids when combined with existing CHARMM biomolecular force fields.
我们展示了CHARMM六元吡喃糖单糖添加剂全原子力场的扩展，以实现对糖苷连接的六元吡喃糖多糖的建模。新的力场参数涵盖1→1、1→2、1→3、1→4和1→6六元吡喃糖糖苷键，以及C(1)异头碳上的O-甲基化，并且开发得与用于蛋白质、核酸和脂质的CHARMM全原子生物分子力场一致。这些参数以分层方式开发，使用包含完整碳水化合物中关键原子的模型化合物，特别是O-甲基四氢吡喃以及由两分子四氢吡喃或一分子四氢吡喃和一分子环己烷组成的糖苷连接二聚体。用于参数优化的目标数据包括由二糖类似物中的Φ/Ψ糖苷二面角定义的完整二维能量表面，该能量表面由MP2/6-31G(d)优化结构上的量子力学MP2/cc-pVTZ单点能量确定（MP2/cc-pVTZ//MP2/6-31G(d)）。为了获得用于Φ/Ψ糖苷二面角的平衡、可转移的二面角参数，考虑了糖苷键中涉及的环碳原子上所有可能手性的表面，从而产生了超过5000个MP2/cc-pVTZ//MP2/6-31G(d)构象能量。作为目标数据还包括振动频率、与水分子的对相互作用能和距离，以及分子内几何结构，包括作为糖苷二面角函数的糖苷价键角的畸变。通过将分子动力学结果与现有实验数据进行比较，在完整二糖上验证了模型化合物优化的力场参数。对于包括晶胞参数和分子内几何结构、水相密度以及与糖苷键相关的水相NMR耦合常数在内的各种性质，实验结果与模型结果取得了良好的一致性。新开发的参数允许单独以及与现有CHARMM生物分子力场结合在包括蛋白质、核酸和/或脂质的异质系统中对线性、支链和环状六元吡喃糖糖苷进行建模。
