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Is the decision based on simple thermodynamics? Bowie NATURE Vol 433, 27,Jan 2005, Seite 367-369 Experimental approach: Integration of designend TM segments into the microsomal membrane degree of membrane integration of the H-segment from SDS– PAGE gels by measuring the fraction of singly (f 1g) versus singly plus doubly (f 2g) glycosylated Lep molecules: p = f1g/(f1g + f2g) The apparent equilibrium constant between the membrane integrated and non-integrated forms : Kapp = f1g/f2g Gapp = -RTlnKapp Apparent free energy (DGapp=‐RT lnKapp) values for test segments with 2‐4 Leu residues Biological hydrophobicity scale Hessa et al., Nature (2005) 433:377‐81 Correlation between the biological and the Wimley–White water/octanol free energy scale Hessa et al., Nature (2005) 433:377‐81 Hydration of small and large hydrophobic solutes The most important physical feature responsible for hydrophobic effects: acting like cavities in the water, the hydrophobic solutes exclude water molecules from the volumes they occupy, and they present regions of space where hydrogen bonding cannot occur Chandler, Nature (2005) 437:640-647 MD-simulations: Snapshot of the solute–water interface for a purely repulsive solute with s 4.5 nm at ambient conditions. Water molecules are shown in red (oxygen) and white (hydrogen). The dashed green circle indicates the apparent solute size R. Mittal & Hummer, PNAS (2008) 105:20130-5 Apolar surface area determines the efficiency of translocon‐mediated membrane‐ protein integration into the endoplasmic reticulum Ojemalm et al Proc.Natl.Acad.Sci.U.S.A 108 (31):E359‐E364, 2011. An amino acid’s contribution to the apparent free energy of membrane‐ insertion is directly proportional to the nonpolar accessible surface area of its side chain, as expected for thermodynamic partitioning between aqueous and nonpolar phases. Unlike bulk‐phase partitioning, characterized by a nonpolar solvation parameter of 23 cal∕mol ∙ Å2, the solvation parameter for transfer from translocon to bilayer is 6–10 cal∕mol ∙ Å2, pointing to important differences between translocon‐guided partitioning and simple water‐to‐membrane partitioning Ojemalm et al Proc.Natl.Acad.Sci.U.S.A 108 (31):E359‐E364, 2011. Ojemalm et al Proc.Natl.Acad.Sci.U.S.A 108 (31):E359‐E364, 2011. Apparent free energy of insertion Ojemalm et al Proc.Natl.Acad.Sci.U.S.A 108 (31):E359-E364, 2011. Apolar surface area determines the efficiency of translocon-mediated membrane-protein integration into the endoplasmic reticulum Ojemalm et al Proc.Natl.Acad.Sci.U.S.A 108 (31):E359-E364, 2011.