Amphiphilic Drug-Like Molecules Accumulate in a Membrane below the Head Group Region

The partitioning behavior of drug-like molecules into biomembranes has a crucial impact on the design and efficacy of therapeutic drugs. Thermodynamic properties connected with the interaction of molecules with membranes can be evaluated by calculating free-energy profiles normal to the membrane surface. We calculated the free-energy profiles of 25 drug-like molecules in a 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine (DOPC) membrane and free energies of solvation in water and heptane using two methods, molecular dynamics (MD) simulations with the Berger lipid force field and COSMOmic, based on a continuum conductor-like screening model for realistic solvation (COSMO-RS). The biased MD simulations (in total ∼22 μs long) were relatively computationally expensive, whereas the COSMOmic approach offered a significantly less expensive alternative. Both methods provided similar results and showed that the studied amphiphilic drug-like molecules accumulate in the membrane, with the majority localized below the head group region. The MD simulations were more lipophilic and gave free-energy profiles that were systematically deeper than those calculated by COSMOmic. To investigate the physical nature of the increased lipophilicity, we analyzed a water/heptane system and identified that it is most likely caused by overestimation of the attractive term of the Lennard-Jones potential in lipid tails. We concluded that COSMOmic can be successfully used for high-throughput computations of global thermodynamic properties, for example, partition coefficients and energy barrier heights, in phosphocholine membranes. In contrast, MD is better for investigating local properties like molecular positioning and orientation in the membrane because they more accurately reflect the complex structure of lipid bilayers. MD is also useful for studies of highly complex systems, for example, drug–membrane–protein interactions

Structural Changes in Ceramide Bilayers Rationalize Increased Permeation through Stratum Corneum Models with Shorter Acyl Tails

Ceramides are indispensable constituents of the stratum corneum (SC), the uppermost impermeable layer of human skin. Ceramides with shorter (four- to eight-carbon acyl chains) fatty acid chains increase skin and model membrane permeability, while further shortening of the chain leads to increased resistance to penetration almost as good as that of ceramides from healthy skin (24 carbons long on average). Here we address the extent to which the atomistic CHARMM36 and coarse-grain MARTINI molecular dynamics (MD) simulations reflect the skin permeability data. As a result, we observed the same bell-shaped permeability trend for water that was observed in the skin and multilayer membrane experiments for model compounds. We showed that the enhanced permeability of the short ceramides is mainly caused by the disturbance of their headgroup conformation because of their inability to accommodate the shorter lipid acyl chain into a typical hairpin conformation, which further led to their destabilization and phase separation. As MD simulations described well delicate structural features of SC membranes, they seem to be suitable for further studies of the SC superstructure, including the development of skin penetration enhancers for transdermal drug delivery and skin toxicity risk assessment studies

Micellization Studied by GPU-Accelerated Coarse-Grained Molecular Dynamics

The computational design of advanced materials based on surfactant self-assembly without ever stepping foot in the laboratory is an important goal, but there are significant barriers to this approach, because of the limited spatial and temporal scales accessible by computer simulations. In this paper, we report our work to bridge the gap between laboratory and computational time scales by implementing the coarse-grained (CG) force field previously reported by Shinoda et al. [Shinoda, W.; DeVane, R.; Klein, M. L. <i>Mol. Simul</i>. <b>2007</b>, <i>33</i>, 27–36] into the HOOMD-Blue graphical processing unit (GPU)-accelerated molecular dynamics (MD) software package previously reported by Anderson et al. [Anderson, J. A.; Lorenz, C. D.; Travesset, A. <i>J. Comput. Phys</i>. <b>2008</b>, <i>227</i>, 5342–5359]. For a system of 25 750 particles, this implementation provides performance on a single GPU, which is superior to that of a widely used parallel MD simulation code running on an optimally sized CPU-based cluster. Using our GPU setup, we have collected 0.6 ms of MD trajectory data for aqueous solutions of 7 different nonionic polyethylene glycol (PEG) surfactants, with most of the systems studied representing ∼1 000 000 atoms. From this data, we calculated various properties as a function of the length of the hydrophobic tails and PEG head groups. Specifically, we determined critical micelle concentrations (CMCs), which are in good agreement with experimental data, and characterized the size and shape of micelles. However, even with the microsecond trajectories employed in this study, we observed that the micelles composed of relatively hydrophobic surfactants are continuing to grow at the end of our simulations. This suggests that the final micelle size distributions of these systems are strongly dependent on initial conditions and that either longer simulations or advanced sampling techniques are needed to properly sample their equilibrium distributions. Nonetheless, the combination of coarse-grained modeling and GPU acceleration marks a significant step toward the computational prediction of the thermodynamic properties of slowly evolving surfactant systems