Influence of Protein Content in Lipid Bilayers on Permeability Calculations for Small Molecular Compounds Using All-Atom Simulations

Sammanfattning

Biological membranes are frequently modeled as homogeneous lipid bilayer structures, often overlooking their natural complexity. This project investigates the impact on membrane structural properties and permeability for small molecules when incorporating polyleucine alpha-helices into lipid bilayers. Molecular Dynamics (MD) simulations were conducted to compare bilayers with and without these helices, focusing on the permeation behavior of two compounds, atenolol and benzoic acid, chosen for their differing log P values. Measuring accurate permeability values provides insight into drug distribution and uptake, which are crucial factors in drug development. Bilayer systems were constructed using CHARMM-GUI, and simulations were performed with GROMACS. Permeability profiles were obtained using umbrella sampling, followed by analysis with the Weighted Histogram Analysis Method (WHAM). Membrane structural properties were analyzed using various analysis tools. The results showed that the inclusion of polyleucine alpha-helices significantly altered membrane structure, as well as the free energy landscapes and permeability profiles of both atenolol and benzoic acid. However, achieving accurate permeability estimates through MD simulations proved challenging due to sampling errors. These observations suggest that incorporating greater molecular complexity into membrane models can lead to enhanced biological relevance and influence molecular interactions. With continued research, such models could provide more precise data and deeper insights into pharmaceutical interactions, improving the drug development process.