Development of GROMOS-Compatible Parameter Set for Simulations of Chalcones and Flavonoids

Chalcones and flavonoids constitute a large family of plant secondary metabolites that have been explored as a potential source of novel pharmaceutical products. While the simulation of these compounds by molecular dynamics (MD) can be a valuable strategy to assess their conformational properties and so further develop their role in drug discovery, there are no set of force field parameters specifically designed and experimentally validated for their conformational description in condensed phase. So the current work developed a new parameter set for MD simulations of these compounds’ main scaffolds under GROMOS force field. We employed a protocol adjusting the atomic charges and torsional parameters to the respective quantum mechanical derived dipole moments and dihedrals rotational profiles, respectively. Experimental properties of organic liquids were used as references to the calculated values to validate the parameters. Additionally, metadynamics simulations were performed to evaluate the conformational space of complex chalcones and flavonoids, while NOE contacts during simulations were measured and compared to experimental data. Accordingly, the employed protocol allowed us to obtain force field parameters that reproduce well the target data and may be expected to contribute in more accurate computational studies on the biological/therapeutical role of such molecules.

查尔酮（Chalcones）与黄酮类化合物（flavonoids）是一类庞大的植物次生代谢物家族，已被探索作为新型药物产品的潜在来源。尽管通过分子动力学（molecular dynamics, MD）模拟这类化合物，是评估其构象特性、进而推进其在药物发现中应用的有效策略，但目前尚无专门针对凝聚相中它们的构象描述而设计并经实验验证的力场参数集。为此，本研究开发了一套全新的参数集，用于在GROMOS力场下对这类化合物的核心骨架开展分子动力学模拟。我们采用了一套标准化流程，分别将原子电荷与扭转参数校准至量子力学衍生的偶极矩与二面角旋转势能曲线。以有机液体的实验属性作为参考基准，对计算得到的参数值进行验证。此外，还开展了元动力学（metadynamics）模拟以评估复杂查尔酮与黄酮类化合物的构象空间，并对模拟过程中的核Overhauser效应（NOE）接触进行量化，与实验数据进行对比。综上，本研究所采用的流程成功获得了能够良好复现目标数据的力场参数，有望为这类分子的生物学/治疗学作用相关高精度计算研究提供助力。