分子动力学模拟在有机污染物毒性作用机制中的应用

The application of molecular dynamics simulations in mechanism of toxicity of organic contaminants

分子动力学模拟(molecular dynamics simulations,MD)是一种基于经典牛顿力学方程的分子模拟方法,常用于研究有机化合物、材料及生物大分子体系,可计算各类体系的宏观性质及各种动力学性质.目前MD模拟逐渐用于研究各类环境污染物与生物大分子的相互作用.通过热力学统计分析污染物与生物大分子的结合模式以及配体结合引起的生物大分子构象变化,能在分子水平上探究污染物的毒性作用机理.基于MD模拟的轨迹文件,采用自由能打分方法可评估污染物与各类受体的结合能力,能够筛选具有特定毒性终点的潜在污染物,从而快速、高通量地进行有机污染物的毒性预测和风险评价.本文介绍了MD模拟的基本原理、常用软件,简述了MD模拟的数据准备和模拟过程,强调了MD模拟的重要细节,进而从污染物与受体生物分子作用角度,重点陈述了MD模拟在研究有机污染物与各类转运蛋白、核受体、代谢酶相互作用中的应用,展望了MD模拟在污染物毒性筛选方面的潜在应用,以期该类方法能更好地服务于污染物的毒性风险评估.

Molecular dynamics（MD） simulations, an established statistical method based on Newton＇s equation of motion, are widely used for studying equilibria and dynamic properties of organic chemicals, materials and in particular biomacromolecular systems. Currently, MD simulations are frequently used to characterize interactions between various environmental contaminants and biomacromolecules. The binding mode of contaminants and conformational changes to target receptors induced by contaminant binding can be probed by MD simulations, and the mechanism of toxicity thus elucidated at the molecular level. The binding affinities of contaminants toward multiple target receptors can be evaluated by various binding free energy methods on the basis of trajectories produce from MD simulations. It is practical to virtually screen potential contaminants toward certain toxic end points, thereby facilitating rapid and high-throughput toxicity prediction and risk assessments. This review provides a basic introduction to the principles of MD simulations and MD software. The data preparation and MD operation are introduced in detail and key factors for MD simulations are described. Recent advances in MD simulations describing the interactions of contaminants with biomacromolecules are comprehensively discussed, and the interactions of organic contaminants with multiple transport proteins, target receptors and metabolic enzymes are highlighted. The perspective of future toxicity screening via MD simulations is provided for better risk assessment of environmental contaminants.