Hydrophobic amino acids are abundant in transmembrane (TM) helices of membrane proteins. Charged residues are sparse, apparently due to the unfavorable energetic cost of partitioning charges into non-polar phases. Nevertheless, conserved arginine residues within TM helices regulate vital functions, such as ion channel voltage gating and integrin receptor inactivation.  The energetic cost of arginine in various positions along hydrophobic helices has been controversial. Potential of mean force (PMF) calculations from atomistic molecular dynamics simulations predict very large energetic penalties, while in vitro experiments with Sec61 translocons indicate much smaller penalties, even for arginine in the center of hydrophobic TM helices.  We present results of computational and experimental studies that permit direct comparison with the Sec61 translocon results.  We find that the Sec61 translocon mediates less efficient membrane insertion of Arg-containing TM helices compared to our computational and experimental bilayer-insertion results due to arginine snorkeling, bilayer deformation, and peptide tilting.

Transmembrane helices containing a charged arginine are thermodynamically stable

245th National Meeting (2013)

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