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产物家族，已被探索为新型医药产品的潜在来源。尽管通过分子动力学（molecular dynamics, MD）模拟这类化合物，可作为评估其构象性质、进而深入挖掘其在药物发现中应用价值的有效策略，但目前尚无专门针对其凝聚相构象描述而设计并经实验验证的力场参数集。为此，本研究基于GROMOS力场，为这类化合物的核心骨架开发了一套全新的MD模拟用参数集。我们采用的优化方案分别将原子电荷与扭转参数适配于量子力学推导得到的偶极矩与二面角旋转曲线，并以有机液体的实验物性作为参考对标计算结果，以完成参数验证。此外，本研究还开展了元动力学（metadynamics）模拟，以探究复杂查尔酮与黄酮类化合物的构象空间；同时对模拟过程中的核欧沃豪斯效应接触（NOE contacts）进行了测量，并与实验数据进行比对。综上，本研究所采用的优化方案成功获得了能够较好复现目标实验数据的力场参数，有望为这类分子的生物学/治疗学相关高精度计算研究提供有力支撑。