# Energetics of the Transmembrane Peptide Sorting by Hydrophobic Mismatch

## TL;DR

This paper explores how transmembrane peptides adjust their position in lipid membranes to reduce hydrophobic mismatch, using molecular dynamics simulations to reveal the underlying energetics.

## Contribution

The study introduces a novel molecular dynamics approach to quantify the energetics of peptide sorting due to hydrophobic mismatch.

## Key findings

- Peptides tilt and diffuse along the membrane to eliminate hydrophobic mismatch.
- The rate of adjustment is directly proportional to the magnitude of the mismatch.
- Free energy profiles show how sorting and tilting contribute to thermally accessible regimes.

## 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 have 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.