Energetics of the Transmembrane Peptide Sorting by Hydrophobic Mismatch

Abstract

Hydrophobic mismatch between a lipid membrane and embedded transmembrane peptides or proteins plays a role in their lateral localization and function. Earlier studies have resolved numerous mechanisms through which the peptides and membrane proteins adapt to mismatch, yet the energetics of lateral sorting due to hydrophobic mismatch has remained elusive due to the lack of suitable computational or experimental protocols. Here, we pioneer a molecular dynamics simulation approach to study the sorting of peptides along a membrane thickness gradient. Peptides of different lengths tilt and diffuse along the membrane to eliminate mismatch with a rate directly proportional to the magnitude of mismatch. We extract the 2-dimensional free energy profiles as a function of local thickness and peptide orientation, revealing the relative contributions of sorting and tilting, and suggesting their thermally accessible regimes. Our approach can readily be applied to study other membrane systems of biological interest where hydrophobic mismatch, or membrane thickness in general, plays a role. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/578561v2_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@e37bdeorg.highwire.dtl.DTLVardef@d94d1aorg.highwire.dtl.DTLVardef@54f1aeorg.highwire.dtl.DTLVardef@c6e0ef_HPS_FORMAT_FIGEXP M_FIG C_FIG