Interactions of Bispyridinium compounds with the DOPC Membrane as revealed by Constraint Dynamics Simulations and Rapid Cyclic Voltammetry

Bispyridinium compounds (BPCs) have important applications as potential pharmaceuticals and antidotes for nerve agent poisoning. These compounds consist of two pyridinium groups linked via the nitrogen atom by an alkyl chain of varying length, while t-butyl groups can substitute the hydrogen atoms of the pyridinium groups. The length of the alkyl chain and the presence or absence of t-butyl groups influence the interactions of BPCs with membranes. These selective interactions of the BPCs with membranes allow us to use the membranes as sensors to trace specific BPCs in blood, water, or other solutions. To confirm the selectivity of membranes to BPCs, we studied the interaction of six BPCs (i.e., having alkyl chain lengths of 1, 5, and 10 with or without t-butyl groups) with the 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membrane when both are in water. We applied Rapid Cyclic Voltammetry (RCV) and Constraint Dynamics Simulations to create rapid cyclic voltammograms and to find the free energy profiles, respectively. Since BPCs have a positive charge of +2e, two negative anions (in our study, iodine anions I-) coexist in the solution. Different BPCs led to differences in the RCV voltammograms (e.g., depression of the capacitance peaks). These differences were further studied by Atomistic Simulations under the influence of an external electric field. Atomistic Simulations revealed a transition from the initial DOPC bilayer orientation to a new one, perpendicular to the first. In the absence of an external electric field, the free energy barriers were larger than 30 kcal/mol for all the examined systems, indicating that it is extremely rare for a BPC to pass through the DOPC membrane. Additionally, the free energy profiles reveal that BPCs prefer to reside in water, followed by the polar part of the DOPC membrane, while BPCs do not prefer the hydrophobic part of the DOPC membrane.