Integral membrane proteins have functional asymmetry i.e. they have two different domains of proteins performing different functions. these proteins have Tyr and Trp amino acid residues at the interface between the lipid and water.Because these amino acids have dual nature that their side chains can interact with both extracellular aqueous environment as well as hydrophobic lipid phase and another generalization about amino acid location relative to bilayer is described by "positive inside rule": The positively charged Lys,His, and Arg residues of membrane proteins occur more commonly on the cytoplasmic phase of membranes.My question is that why only positively charged amino acids are faced towards cytoplasm why not negatively charged amino acids or other amino acids are favoured here?

  • $\begingroup$ Yes, I have a reference for this claim.from the Lehninger Principles of Biochemistry Chapter 11 Biological membranes and Transport. and Sorry for the late acceptance of answers because it did not know it actually how to accept answers by using green trick but know i became familiar with this so i accepted the answers. @Chris $\endgroup$ Commented Mar 24, 2014 at 20:35

1 Answer 1


Some thoughts on this. First of all, the positive-inside rule, proposed by Gunnar von Heijne, is an empirical rule based upon observations, not one derived from theoretical considerations, so any explanation is simply an attempt at a rationalisation.

Having said that, here are three of those rationalisations:

  • the membrane potential is usually negative inside. This will create an electrostatic tendency for basic amino acid side chains to stay inside.

  • most phospholipid head groups are either neutral or anionic (phosphatidylserine, when the phosphate is included). Again an electrostatic force favouring basic residues inside since to move them out would require overcoming their interaction with the negatively-charged membrane surface

  • the pK values of the basic side chains (lysine and arginine) are much further from 7 than are those of the acidic side chains, so, since charged residues must be neutralised to get them through the bilayer, it is more energetically unfavourable to deprotonate basic side chains than it is to protonate acidic ones.

  • $\begingroup$ The environment inside the cell is reducing. $\endgroup$
    – biogirl
    Commented Mar 26, 2014 at 4:11
  • $\begingroup$ @biogirl yes, it is, but acid-base equilibria are not redox reactions. I don't understand what your point is. $\endgroup$
    – Alan Boyd
    Commented Mar 26, 2014 at 8:54
  • $\begingroup$ I thought reducing environment would lead to addition of protons. $\endgroup$
    – biogirl
    Commented Mar 26, 2014 at 9:07

You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .