Synergistic Effects of IMX-104 Components in Membrane Absorption: A Computational Study

New insensitive munitions such as IMX-104 formulations are being developed to improve the safety suffering from accidental stimulations. Experimental data indicated the synergistic toxicity of 2,4-dinitroanisole (DNAN) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in IMX-104, which increased the concern about its environmental and health threats. Indeed, little is known about the synergistic mechanism. Here, we investigated the membrane absorption of DNAN and RDX as the first step toward uncovering synergistic toxicity. The permeability coefficient, transmembrane time, and liposome–water partition coefficient were calculated by the umbrella sampling technique. The results show that component RDX in the IMX-104 formulation promotes the membrane absorption of another more toxic component DNAN, suggesting that the synergistic toxicity effect of IMX-104 may emerge from their membrane adsorption stage. In detail, the integrating free-energy curves show that DNAN, RDX, or their mixture in membranes would promote subsequent molecules passing through membranes. For the mixture of DNAN and RDX, RDX was absorbed by the membrane before DNAN. Postabsorbed DNAN tends to stay around RDX, which is due to the strong van der Waals (VDW) interaction between them. RDX stabilized under phospholipid headgroups limits the overflow of DNAN from the membrane, which results in 11% more absorption of DNAN by the membrane than in the case of the pure DNAN system.为提升弹药在意外刺激下的安全性能，新型钝感弹药（insensitive munitions）如IMX-104配方正处于研发阶段。实验数据表明，IMX-104中的2,4-二硝基茴香醚（2,4-dinitroanisole, DNAN）与六氢化-1,3,5-三硝基-1,3,5-三嗪（hexahydro-1,3,5-trinitro-1,3,5-triazine, RDX）存在协同毒性，这引发了学界对其环境与健康威胁的更多担忧。目前关于二者协同毒性的作用机制仍知之甚少。本研究以DNAN与RDX的膜吸收过程作为揭示其协同毒性机制的首要步骤，通过伞形采样（umbrella sampling）技术计算了两种物质的渗透系数、跨膜时间以及脂质体-水分配系数。结果显示，IMX-104配方中的RDX组分可促进毒性更强的另一组分DNAN的膜吸收过程，这表明IMX-104的协同毒性效应可能产生于二者的膜吸附阶段。具体而言，整合自由能曲线表明，膜内的DNAN、RDX或二者混合物均可促进后续分子跨膜转运；对于DNAN与RDX的混合体系，RDX会先于DNAN被细胞膜吸附，后续吸附的DNAN倾向于聚集在RDX周围，这源于二者之间强烈的范德华（van der Waals, VDW）相互作用。RDX在磷脂头部基团下的稳定作用限制了DNAN从膜内溢出，使得DNAN的膜吸收量相较于纯DNAN体系提升了11%。