Evaluating membrane affinity by integrating protein orientations

Energetic interactions of a protein with lipid bilayers determine its propensity to reside in the membrane. Here we seek to evaluate the membrane interactions for EMAPII, a protein found to be released from the cell by unknown mechanisms, as well as several other proteins. Using a knowledge-based coarse-grained membrane potential, we calculate the free energy profiles for these proteins by integrating out the orientation degrees of freedom. Due to the invariance of energy under in-plane rotations about the membrane normal, the orientation space can be reduced to two dimensions and mapped onto the surface of a unit sphere, thus making visualization, sampling and integration more convenient. The integrated free energy profiles determine the relative probabilities along the membrane normal for the proteins regardless of their orientations, and display distinctive characteristics for membrane proteins and water-soluble proteins. The membrane interactions for EMAPII exhibit typical features of a water-soluble protein, with a high energetic barrier to enter or cross the membrane. Our results thus suggest that similar to the non-classical export of FGF1, the release of EMAPII would involve more complicated mechanisms than simple passive diffusion across the membrane.