Hydrophobic MismatchLateral Pressure

These lecture notes are taken from current literature. See special edition of BBA, (biomembranes) 1666 2004.

Our previous lectures have discussed in detail what is meant by “non-bilayer” structures (really non-lamellar because inverted hexagonal phase is somewhat bilayer in nature). This figure reviews how shape is related to mesophase.

Effects of “non-bilayer” lipids on membrane proteins:•Curvature Stress – discussed in detail in previous lectures•Hydrophobic mismatch•Packing Defects•Lateral Pressure Profiles

Our Motivation: To understand how lipids and lipid-protein interactions drive membrane protein function and membrane-protein interactions

Different types of “membrane” proteins

Hydrophobic Mismatch

When the hydrophobic region of a protein or peptide (length) differs from that of the bilayer, the bilayer will adapt and curve to “cover” the hydrophobic surface area of the protein.

Sometimes the protein will also change it’s conformation or tilt.

Changes in bilayer shape are related to both the curvature near the protein as well as “global” lipid bilayer thinning or thickening.

The WALP peptide are the classic study of effects of hydrophobic mismatch both for membrane properties and peptide tilt.

WALP (ALA and LEU with TRP to anchor at the bilayer interface)

Protein SortingConformational Changes

Rafts and Lateral organization

Hydrophobic Mismatch

Hydrophobic Mismatch: Protein Folding and Sorting

Hydrophobic Mismatch Effects: Gramicidin and Rhodopsin Extensively Studied

VpU

Tilt of protein can change as a function of membrane thickness

Oligomerization states can change

Conformations can change

Hydrophobic Mismatch

Question: How do non-lamellar lipids affect hydrophobic mismatch?

Packing Defects/Insertion Sites

Several studies have suggested that the presence of the non-lamellar lipids will produce bilayer packing defects that can influence peripheral membrane proteins.

Asymmetry can produce a physical curvature

Symmetric distribution of non-lamellar lipid

Examples of protein binding effected by lipids with negative spontaneous Curvature:•phospholipase A2•Protein kinase C•Apolopophirin II•CTP:phosphocholine cytidylyltransferase

Lateral Pressure

In reality, the spontaneous curvature, defect packing and lateral pressure concepts are related.

Lateral Pressure Profile in membranes.First proposed in 1960s.

Large negative pressure due to the cohesive hydrophobic interfacial tension is localized at the polar-apolar interface

Overall Lateral Pressure is zero (integration over profile must be zero)

There curvature stress is related to the lateral pressure profile via the torque tension, , which is the first moment of the lateral pressure.

Remember, spontaneous curvature is not real curvature, it is a representation about stored energy/forces in the bilayer. Forces can be related to pressures.

z zdz C o2

Lateral pressureSpontaneous curvature

Lateral Pressure

Changes in the lateral pressure profile will only affect those membrane proteins whose function involves a conformational change that is accompanied by a depth dependent variation in cross-sectional area.

Lateral Pressure

Examples of Proteins Affected by Lateral pressure profiles:

•leader peptidase 2-75•KcsA

KcsA – symmetric tetramer with each monomer consisting of an N-terminal helix at the membrane interface, a transmembrane helix, followed by a short pore helix leading to the selectivity filter in the tetrameric structure

The KcsA tetramer is stable in SDS, but can be denatured by heat or TFE-trifluoroethanol. KcsA preferentially interacts with PE and PG lipids.

Tetramer stability: detergent < cylindrical PC < PC/PG (7:3) < PE/PG (7:3)

TFE interactions with lipid bilayers interact with head group region, decreasing the acylchain order

DOPC DOPG/DOPE

DOPC PG/PE

Concept: an “hour-glass” shaped oligomer is stabilized in bilayer mixtures with PE. Addition of TFE perturbs the lateral pressure profiles