Paulikat, M. | Search bioRxiv

bioRxiv2023

Physical Chemistry of Drug Permeation through the Cell Membrane with Atomistic Detail

We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the anti-malaria, FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for drugs action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/550356v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@d1f5b9org.highwire.dtl.DTLVardef@5b6b0forg.highwire.dtl.DTLVardef@1d1b55borg.highwire.dtl.DTLVardef@d96b52_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Proton Transfers to DNA in Native Electrospray Ionization Mass Spectrometry: A QM/MM Study.

Native electrospray ionization - ion mobility mass spectrometry (N-ESI/IM-MS) is a powerful approach for low-resolution structural studies of DNAs in the free state and in complex with ligands. Solvent vaporization is coupled with proton transfers from ammonium ions to the DNA resulting in a reduction of the DNA charge. Here we provide insight on these processes by classical MD and QM/MM free energy calculations on the (GpCpGpApApGpC) heptamer, for which a wealth of experiments is available. Our multiscale simulations, consistent with experimental data, reveal a highly complex scenario: the proton either sits on one of the molecules or is fully delocalized on both, depending on the level of hydration of the analytes and on size of the droplets formed during the electrospray experiments. This work complements our previous study on the intramolecular proton transfer on the same heptamer occurring after the processes studied here, and, together, provide a first molecular view of proton transfer in N-ESI/IM-MS. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/511116v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@3d85d3org.highwire.dtl.DTLVardef@11ce1d1org.highwire.dtl.DTLVardef@12d932corg.highwire.dtl.DTLVardef@1196de8_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗