Molecular Simulation Studies on the Interactions of 2,4,6-Trinitrotoluene and Its Metabolites with Lipid Membranes

Abstract

The penetration of chemicals into biological membranes is a key factor in the determination of their possible effects on organisms; this complex process involves mainly the interaction between chemicals and membranes. Here, we reported the interaction between a highly toxic class of explosives [2,4,6-trinitrotoluene (TNT) and its metabolites] and lipid membranes using molecular dynamics simulations. We calculated the permeability coefficient, transmembrane time, and liposome–water partition coefficient by integrating free-energy curves for all species. The results showed that TNT had a lower transmembrane capacity than its metabolites. Based on the liposome–water partition coefficient, we demonstrated that the membrane affinity of TNT is larger than that of its diamino metabolites but less than that of its monoamino metabolites. This result can qualitatively explain the difference of bioconcentration factors in experiments. The accumulation of TNT and metabolites in membranes can change the membrane structure, such as the area per lipid, the thickness of lipid bilayers, and the order of lipid tails and, further, the penetration of water. All of these are closely related to the interactions (mainly hydrogen bonds) of TNT and metabolites with lipid and water molecules. This work has a certain significance for understanding the toxicity of TNT and its metabolites.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…Antiseptic Picloxydine, Octenidine, Miramistin [470], Polyhexamethylene Biguanide [471] Insecticide Parathione [132], Fipronil [472], Dibutyl succinate [203] Former Drugs d-sotalol, cisapride [473], piracetam (status varies among countries) [474], ORG-12962 [199] Toxic xenobiotic Polybrominated-diphenyl-ethers [475], Bisphenol [476], Perfluoroalkyls [477], nitroaromatic explosives (TNT,2A, and 24DA) [478][479][480][481], 1,4-Dioxane [482], Benzo[a]pyrene [483] Nanomaterials Graphene [484][485][486][487], Carbon Dots [488], Phosphorene Oxide Nanosheets [489], Gold Nanoparticles [490][491][492], Titanium Dioxide Nanoparticles [493], Generic Nanoparticles (coarse grained) [494], Fullerene [495][496][497][498], Previous reviews [499] Polymers Poly(ethyleneoxide)-Poly-(propylene oxide) [500], polyethylenimine [501], Poloxamer [502,503], Pluronics [504,505], poly(ethyleneglycol)-desferrioxamine/ gallium [506], PEG functionalized with carbochydrates [507] and peptides…”

Collective absorption of 2,4,6-trinitrotoluene into lipid membranes and its effects on bilayer properties. A computational study

“…The basis for selection is not the actual physiological concentration, but our previous simulation results for judging the formation of aggregates. 16 As we all know, a small piece of phospholipid membrane and its surrounding waters can be only considered in simulations, so TNT concentrations here cannot be directly compared with those in real physiological conditions especially the different size scales. In addition, to minimize the influence of box size on the result under the high TNT concentration, the large-size membrane (consisted of 512 POPC lipids) was used.…”

“…6b, and the PMF prole of TNT though the pure POPC membrane was taken from our previous work. 16 In the pure POPC membrane, the free energy of an incoming TNT molecule (DG water ) decreases by À12.0 kJ mol À1 from the aqueous phase into the interior of lipid bilayers, without an obvious barrier in the membrane-water interface. The prole had a minimum (z min ) at z ¼ 1.51 nm, just below the head groups of lipids.…”

“…For TNT density proles, we found that a part of TNT molecules had entered the membrane in the rst 30 ns of simulations with the density peak at z ¼ AE1.5 nm, well corresponding to the results from our previous work. 16 Aer a few hundred nanoseconds of simulations, most of TNT molecules are absorbed into the membrane from the bulk water. At high concentration (14%-system, Fig.…”

“…Golius et al 15 calculated the partition coefficient for several explosives (such as TNT, dinitrotoluene, dinitroanisole). Our recent work 16 studied the thermodynamics of TNT and its metabolites passively across lipid membranes. We found the accumulation of TNT and metabolites in the membrane results in the increase of water penetration, which is concentration-dependent.…”