Modeling Charged Protein Side Chains in Lipid Membranes

The recent perspectives on membrane protein insertion, protein–bilayer interactions, and amino acid side hydrophobicity (J. Gen. Physiol. 129:351–377) have provided a great opportunity to explore an important problem that has challenged our basic understanding of protein–lipid interactions and membrane protein function. Biological membranes consist primarily of lipid bilayers that exhibit hydrophobic cores which present significant barriers to all polar and charged species. This essential character of membranes was brought into question after the proposal of the “paddle” model of voltage-gated ion channel gating (Jiang et al., 2003) in which voltage-sensing domains, containing multiple charged arginine (Arg) side chains, were supposed to move across the core of a lipid membrane, despite theoretical energy cost predictions of 100s of kcal/mol (Grabe et al., 2004). This discrepancy underscores the importance of critically evaluating all models in terms of the fundamental...