CHEM 114A: Chapter 9 - Lecture 2

Membrane Dynamics Overview

• Biological membranes behave as dynamic, fluid assemblies rather than rigid walls.
• Lipids (and many proteins) are in continuous motion, driven mainly by rotation about C–C bonds and fluctuating van-der-Waals interactions.
• Two principal modes of lipid motion:
  • Lateral diffusion: side-to-side movement within the same leaflet.
  • Transverse diffusion (flip-flop): lipid migrates from one leaflet to the opposite leaflet; intrinsically slow and usually protein-catalysed.

Types of Lipid Movements

Lateral Diffusion

• Rapid (milliseconds), highly temperature- and composition-dependent.
• Steric hindrance is minimized because lipid packing is imperfect and heterogeneous (molecular-dynamics images reveal non-uniform acyl-chain spacing).
• Influencing factors: size and type of polar head group, acyl-chain length, degree of unsaturation, cholesterol content.

Transverse Diffusion (Flip-Flop)

• Requires a lipid to transport a polar/charged head through the hydrophobic core ⇒ energetically unfavourable.
• Enzymatically facilitated by membrane proteins (flippases, floppases, scramblases).
• Often coupled to signalling (e.g., exteriorisation of phosphatidylserine during apoptosis).
• Creates/erases membrane asymmetry.

Measuring Lateral Diffusion – FRAP

• Fluorescence Recovery After Photobleaching (FRAP) quantifies lipid mobility.
  1. Label lipids or membrane surface with covalently attached fluorophores.
  2. Observe uniform fluorescence using a fluorescence microscope.
  3. Focus a laser to photobleach a defined region → local fluorescence lost.
  4. Monitor fluorescence recovery as unbleached lipids laterally diffuse into the bleached zone.
• Fluorescence intensity vs. time yields the diffusion coefficient $D\;(\mathrm{cm^2\,s^{-1}})$ (commonly via $D=\frac{w^2}{4t<em>{1/2}}$ where $w$ = radius of bleached spot, $t</em>{1/2}$ = half-time for recovery).

Membrane-Protein Interplay & Asymmetry

• Lipid–protein interactions modulate lipid mobility (proteins can corral or cluster lipids).
• Membrane proteins are asymmetrically distributed; inner vs. outer leaflets possess distinct lipid compositions (e.g., sphingomyelin enriched outside).
• Controlled flip-flop of specific lipids can trigger intracellular cascades.

Heterogeneity of Lipid Composition Across Organelles

• Lipid makeup is organelle-, cell-, and species-specific.
• Example table (colour-coded in lecture):
  • Cholesterol varies markedly—low in inner mitochondrial membrane, high in plasma membrane.
  • Functional demands dictate composition (signalling, curvature, permeability).

Phase Transition & Melting Temperature (T_M)

• Membrane lipids exhibit a gel–to–liquid-crystal transition.
• $T<em>M$ depends on chain length (↑ carbons ⇒ ↑$T</em>M$) and unsaturation (cis-double bonds introduce ~$30^\circ$ kink ⇒ ↓$T_M$).
• Below $T_M$: "solid-like"; tight packing, maximised van-der-Waals forces.
• Above $T_M$: "fluid-like"; increased molecular motion.

Temperature Adaptation

• Many non-homeothermic organisms remodel lipid composition to maintain fluidity (e.g., deer hoof lipids altered in winter).

Structural Categories of Membrane Lipids

1. Phospholipids (Glycerophospholipids)
2. Sphingolipids
3. Sterols

(Triglycerides excluded—they are storage, not structural.)

Phospholipids (Glycerophospholipids)

• Core: glycerol-3-phosphate.
  • C1 & C2: esterified fatty acids.
  • C3: phosphate + variable head group $X$.
• Head-group variants (list from table):
  • $X=\mathrm{H}$ ⇒ phosphatidic acid (rare).
  • $X=\mathrm{CH<em>2CH</em>2N^+(CH<em>3)</em>3}$ ⇒ phosphatidylcholine (abundant).
  • $X=\text{myo-inositol}$ ⇒ phosphatidylinositol (signalling lipid).
  • …others: phosphatidylserine, phosphatidylethanolamine, etc.
• Typical example: 1-stearoyl-2-oleoyl-3-phosphatidylcholine
  • C1: saturated $C_{18}$ stearic acid.
  • C2: $C_{18}$ oleic acid with cis-double bond between C9–C10 (kink visible in space-filling model).

Sphingolipids

• Backbone: sphingosine ((C_{18}) amino-alcohol with trans double bond).
• Acylation of sphingosine’s $\mathrm{NH_2}$ with a fatty acid ⇒ ceramide (structural hub of sphingolipid families).

Sphingomyelins

• Ceramide + phosphocholine (or phosphoethanolamine) head.
• 10–20 % of plasma membrane lipids.
• Form multilamellar myelin sheaths around neurons—electrical insulation.

Glycolipids

Cerebrosides

• Ceramide + single sugar (glucose or galactose).
• Non-ionic (no phosphate).

Gangliosides

• Ceramide + complex oligosaccharide containing sialic acid linked to the second sugar.
• Structural diversity: >100 gangliosides (GM1, GM2, GM3… ― nomenclature reflects sugar composition).
• ≈6 % of human brain lipids.
• Large polar head protrudes far beyond membrane → critical in cell–cell recognition & signalling.

Sterols

Core Structure

• Four fused rings $A\,B\,C\,D$: cyclopentanoperhydrophenanthrene.

Cholesterol

• Dominant sterol in animals; 30–40 % of plasma-membrane lipid.
• Short iso-octyl side chain—not a long acyl tail.
• Inserts between phospholipids → disrupts close packing, increasing fluidity and broadening phase-transition temperature.
• Provides precursor for many bioactive steroids.

Steroid Derivatives (all synthesised from cholesterol)

• Aldosterone – electrolyte balance & kidney function.
• Cortisol – stress response, metabolism.
• Testosterone / Estradiol – male & female sex hormones.

Ethical / Physiological Implications & Real-World Connections

• Proper flip-flop regulation is essential; misregulation of phosphatidylserine exteriorisation signals apoptosis.
• Cholesterol’s dual role: vital for membrane fluidity yet implicated in atherosclerosis—balance is key in diet/medicine.
• Myelin integrity dependent on sphingomyelin; demyelinating diseases (e.g., multiple sclerosis) involve lipid dysregulation.
• Ganglioside accumulation defects (e.g., Tay–Sachs disease) underscore importance of enzymatic lipid turnover.

Numerical & Statistical Highlights

• Lateral diffusion measured by FRAP can yield $D \approx 10^{-8}\;\text{to}\;10^{-9}\;\mathrm{cm^2\,s^{-1}}$ (typical for plasma membranes).
• Sphingomyelins: 10–20 % of plasma-membrane lipids.
• Gangliosides: ≈6 % of human brain lipids.
• Cholesterol: 30–40 % of plasma-membrane lipids.

Conceptual Connections to Previous Lectures

• Builds on lipid physical chemistry (acyl chain length, unsaturation, $T_M$) introduced earlier.
• Extends discussion of amphipathic molecules and micelle/bilayer energetics.
• Re-uses knowledge of myo-inositol (secondary messenger roles) and van-der-Waals forces.

Key Take-Away Equations & Definitions

• Diffusion coefficient (FRAP): $D=\frac{w^2}{4t_{1/2}}$.
• Melting temperature concept: fluid phase exists for T>TM; gel phase for $T<T</em>M$.
• Ceramide = sphingosine + fatty acid (amide linkage).
• Sphingomyelin = ceramide + phosphocholine/ethanolamine.
• Ganglioside = ceramide + complex oligosaccharide + sialic acid.