Coarse-Grained Molecular Dynamics Simulations of the Energetics of Helix Insertion into a Lipid Bilayer

Experimental and computational studies have indicated that hydrophobicity plays a key role in driving the insertion of transmembrane α-helices into lipid bilayers. Molecular dynamics simulations allow exploration of the nature of the interactions of transmembrane α-helices with their lipid bilayer environment. In particular, coarse-grained simulations have considerable potential for studying many aspects of membrane proteins, ranging from their self-assembly to the relation between their structure and function. However, there is a need to evaluate the accuracy of coarse-grained estimates of the energetics of transmembrane helix insertion. Here, three levels of complexity of model system have been explored to enable such an evaluation. First, calculated free energies of partitioning of amino acid side chains between water and alkane yielded an excellent correlation with experiment. Second, free energy profiles for transfer of amino acid side chains along the normal to a phosphatidylcholine bilayer were in good agreement with experimental and atomistic simulation studies. Third, estimation of the free energy profile for transfer of an arginine residue, embedded within a hydrophobic α-helix, to the center of a lipid bilayer gave a barrier of ∼15 kT. Hence, there is a substantial barrier to membrane insertion for charged amino acids, but the coarse-grained model still underestimates the corresponding free energy estimate (∼29 kT) from atomistic simulations (Dorairaj, S., and Allen, T. W. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 4943-4948). Coarse-grained simulations were then used to predict the free energy profile for transfer of a simple model transmembrane α-helix (WALP23) across a lipid bilayer. The results indicated that a transmembrane orientation was favored by about -70 kT. © 2008 American Chemical Society.