Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Center for Drug Design, University of Minnesota, Minneapolis, MN 55455, USA.
Molecules. 2022 Apr 19;27(9):2616. doi: 10.3390/molecules27092616.
Molecular mechanics force field calculations have historically shown significant limitations in modeling the energetic and conformational interconversions of highly substituted furanose rings. This is primarily due to the gauche effect that is not easily captured using pairwise energy potentials. In this study, we present a refinement to the set of torsional parameters in the General Amber Force Field () used to calculate the potential energy of , , and -fluorinated nucleosides. The parameters were optimized to reproduce the pseudorotation phase angle and relative energies of a diverse set of and fluoro substituted furanose ring systems using quantum mechanics umbrella sampling techniques available in the IpolQ engine in the Amber suite of programs. The parameters were developed to be internally consistent with the force field and the TIP3P water model. The new set of angle and dihedral parameters and partial charges were validated by comparing the calculated phase angle probability to those obtained from experimental nuclear magnetic resonance experiments.
分子力学力场计算在模拟高度取代的呋喃糖环的能量和构象转换方面一直存在显著的局限性。这主要是由于不能轻易使用成对能量势来捕获的 gauche 效应。在这项研究中，我们对通用 Amber 力场 () 中用于计算 、 和 -氟化核苷势能的扭转参数集进行了改进。使用 Amber 程序套件中的 IpolQ 引擎中的量子力学伞状采样技术，我们对参数进行了优化，以重现各种 和氟取代的呋喃糖环系统的假旋转相角和相对能量。这些参数是为了与 力场和 TIP3P 水模型内部一致而开发的。通过将计算得到的相角概率与实验核磁共振实验得到的相角概率进行比较，验证了新的角度和二面角参数和部分电荷。
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