(531a) Molecular Simulation Methods to Understand the Partition Behavior of Charged Solutes in Biomembranes

Interactions of charged solutes with biomembranes (liposomes, lipid bilayers) are far less investigated than the interactions of neutral solutes. However, they are of outstanding interest for toxicological studies, environmental science, drug design and the food industry. In the drug industry for instance, more than 60% of pharmaceutical substances are ionizable. Furthermore, the technical separation of charged compounds from aqueous solutions is very challenging. Especially, for biotechnology applications efficient separation steps are crucial for the establishment of new processes.
The partition behavior of charged solutes between liposomes or micelles and aqueous solutions is not fully understood yet. Different theories exist that explain the transport mechanism of charged solutes. In theoretical studies it was shown that the charged solutes are hydrated in lipid bilayers, so called “water fingers” are formed. Another theory states that charged solutes are transported as ion-pairs. A third possibility is the protonation of charged solutes before transport into membranes.
In this work molecular dynamics (MD) simulations were used to understand the transport mechanism of charged solutes into lipid bilayers. Free energy profiles were calculated with different techniques. For the first time partition coefficients from calculated free energy profiles are rigorously compared to experimental results. The predictions are in good agreement with experimental results if the force filed is precise enough and the simulation set-up was appropriate. For instance, the simulation time to reach an equilibrated free energy profile was carefully investigated.
The MD simulations are used to investigate the pH dependence of partition coefficients and the salt concentration influence on partition of charged solutes. Experimentally it was shown that partition coefficients of charged solutes can increase with increasing salt concentration. However, the mechanism causing this dependency is not understood. We simulated the charged solutes in different configurations (protonated, ionized, ion-pair) at different salt concentrations. By comparing the predicted partition coefficients with experimental results, we could elucidate the partition mechanism. Especially, it was found that ion-pair formation does influence the result.
Additionally, the recently introduced extension of the thermodynamic model COSMO-RS to micelles and bilayers (termed COSMOmic) was investigated to show its comparability with MD results and its applicability to charged solutes.