Exploring Free Energy Landscapes for Protein Partitioning into Membrane Domains in All-Atom and Coarse-Grained Simulations.

It is known that membrane environment can impact the structure and function of integral membrane proteins. As such, elucidation of the thermodynamic driving forces governing protein partitioning between membrane domains of varying lipid composition is a fundamental topic in membrane biophysics. Molecular dynamics simulations provide valuable tools for quantitatively characterizing the free energy landscapes governing protein partitioning at the molecular level. In this study, we propose an efficient simulation methodology for the calculation of free energies for the partitioning of transmembrane proteins between liquid-disorder (L_d) and liquid-ordered (L_o) domains in all-atom (AA) phase-separated lipid bilayers. The computed potential of mean force defining the equilibrium partition coefficients is compared for AA and coarse-grained systems. Energy decomposition is used to identify differences in the underlying thermodynamics. Our findings highlight the importance of employing AA models to accurately estimate relevant free energy changes during protein translation between membrane domains.