GeTFEP: A general transfer free energy profile of transmembrane proteins

Abstract

Transfer free energy (TFE) of amino acid side-chains from aqueous environment into lipid bilayers is an important contributing factor in determining the thermodynamic stability of a transmembrane protein (TMP). It also provides the basis for understanding TMP folding, membrane insertion, and structure-function relationship. We have derived a General Transfer Free Energy Profile (GeTFEP) from β-barrel transmembrane proteins (TMBs). GeTFEP is in good agreement with previous experimentally measured and computationally derived scales. Besides, we show that GeTFEP is applicable to α-helical transmembrane proteins (TMHs) as well by successfully predicting the number and length of transmembrane segments. Application of GeTFEP reveals significant insights into the folding and insertion processes of TMBs. Furthermore, we can predict structurally and/or functionally interesting sites of TMBs using GeTFEP.

Folding-Degradation Relationship of a Membrane Protein Mediated by the Universally Conserved ATP-Dependent Protease FtsH

“…However, from the hydrophobicity analysis of GlpG using the membrane depth-dependent hydrophobicity scale 49,50 , and Hessa-von Heijne and Wimley-White scales determined near the center of the bilayer5 1,52 (Figure 5e), we noticed that the N-terminal TM1 helix was much more hydrophobic than the C-terminal TM6 helix by 4–10 kcal/mol. This fact raises a possibility that, in addition to the conformational stability that resists unfolding, the hydrophobicity of the TM segment near the marker that would resist membrane dislocation may also control degradation.…”

“…On the basis of the asymmetric unfolding energy landscape and the sensitivity of the degradation rate to the stability change, we reasoned that the slow degradation of GlpG with the N-terminal degradation markers (Figure 3d) was caused by the higher conformational stability of the N-subdomain. However, from the hydrophobicity analysis of GlpG using the membrane depth-dependent hydrophobicity scale, 49,50 and Hessa-von Heijne and Wimley-White scales determined near the center of the bilayer 51,52 (Figure 5e), we noticed that the Nterminal TM1 helix was much more hydrophobic than the Cterminal TM6 helix by 4−10 kcal/mol. This fact raises a possibility that, in addition to the conformational stability that resists unfolding, the hydrophobicity of the TM segment near the marker that would resist membrane dislocation may also control degradation.…”

High-resolution structure prediction of β -barrel membrane proteins

“…Computational studies have contributed to expand our knowledge of βMPs by successfully predicting βMP sequences at a genomewide scale (14,15), identifying transmembrane (TM) segments (16,17) and uncovering sequence and spatial motifs (18,19). The stability, oligomerization state, protein-protein interaction interfaces, and the transfer free energy of residues in the TM regions of βMPs can also be accurately computed (20)(21)(22)(23)(24)(25)(26).…”