Proteins can be attached to the membrane by various methods. These include acyl chains, GPI anchors, and prenylation. Proteins can also interact with the entire width of the membrane, as is observed with integral membrane proteins.
Acyl chains are attached to the N-terminus of the protein, allowing the chain to insert into the inner membrane leaflet. The is a method of anchoring peripheral membrane proteins, within the cell. This anchoring method is not able to be used extracellularly, due to the more hostile environment.
Prenylation is another attachment that can be used to attach proteins to the inner membrane leaflet. A prenyl chain is bound to the C-terminal, post-translationally. This post-translational modification is only able to be done where the terminal amino acid is a cysteine - the terminal a-a-X residues are cleaved off (where a is an aliphatic amino acid, and X is any amino acid).
Glycosyl phosphatidylinositol (GPI) anchors are formed by C-terminal modification of the protein, adding an oligosaccharide and inositol by ethanolamine bond. As this form of attachment imitates the fatty acids from lipids more strongly (with two chains), this GPI anchor bond is stronger. Therefore, this type of attachment is used on the exterior face of the membrane. Due to this anchoring outward-facing proteins, it is frequently used for enzymes, identification proteins, and other similar interactions.
Proteins can also be inserted to form part of the membrane. This is possible during protein translocation, allowing transmembrane domains to be inserted into the membrane by the translocator (SecY or Sec61). Residues found near the boundary of the membrane may have larger (aromatic) side chains, helping to prevent the lateral movement of the protein. The residues that interact with the core of the membrane will be hydrophobic, allowing for successful interactions to form. If hydrophilic residues were found on the membrane-interacting domain, it would not be possible for the protein to insert into the membrane due to the strong repulsion that would be observed.