Modeling of the structural features of integral‐membrane proteins reverse‐environment prediction of integral membrane protein structure (REPIMPS)

Abstract

The Profiles‐3D application, an inverse‐folding methodology appropriate for water‐soluble proteins, has been modified to allow the determination of structural properties of integral‐membrane proteins (IMPs) and for testing the validity of solved and model structures of IMPs. The modification, known as reverse‐environment prediction of integral membrane protein structure (REPIMPS), takes into account the fact that exposed areas of side chains for many residues in IMPs are in contact with lipid and not the aqueous phase. This (1) allows lipid‐exposed residues to be classified into the correct physicochemical environment class, (2) significantly improves compatibility scores for IMPs whose structures have been solved, and (3) reduces the possibility of rejecting a three‐dimensional structure for an IMP because the presence of lipid was not included. Validation tests of REPIMPS showed that it (1) can locate the transmembrane domain of IMPs with single transmembrane helices more frequently than a range of other methodologies, (2) can rotationally orient transmembrane helices with respect to the lipid environment and surrounding helices in IMPs with multiple transmembrane helices, and (3) has the potential to accurately locate transmembrane domains in IMPs with multiple transmembrane helices. We conclude that correcting for the presence of the lipid environment surrounding the transmembrane segments of IMPs is an essential step for reasonable modeling and verification of the three‐dimensional structures of these proteins.