Computational analysis of membrane proteins: the largest class of drug targets

Abstract

Given the key roles of integral membrane proteins as transporters and channels, it is necessary to understand their structures and, hence, mechanisms and regulation at the molecular level. Membrane proteins represent approximately 30% of all proteins of currently sequenced genomes. Paradoxically, however, only approximately 2% of crystal structures deposited in the protein data bank are of membrane proteins, and very few of these are at high resolution (better than 2A). The great disparity between our understanding of soluble proteins and our understanding of membrane proteins is because of the practical problems of working with membrane proteins - specifically, difficulties in expression, purification and crystallization. Thus, computational modeling has been utilized extensively to make crucial advances in understanding membrane protein structure and function.

FIGURE 1

Two examples of membrane proteins. KcsA (left) (PDB: 1K4C) is a voltage-gated K⁺-selective α-helical protein. OmpA (right) (PDB: 1QJP) is an example of a β-barrel membrane protein. The dashed lines indicate the position of the bilayer.

FIGURE 2

Illustration of a membrane protein (KcsA, shown in purple) embedded in a lipid bilayer. For clarity, the water molecules on either side of the lipid bilayer have not been included. The hydrocarbon core of a membrane is typically ~25–30 Å wide with the headgroups spanning ~10 Å. The polar head groups of the lipids face the aqueous environment on both sides of the membrane, whereas their hydrophobic chains form the insulating interior of the bilayer. Owing to the ester carbonyls and water associated to the lipid headgroups, lipid molecules possess electrical dipoles, which result in a considerable electrical potential (positive inside the bilayer). Figure generated using KcsA crystal structure, PDB: 1K4C.