Membranes & Membrane Proteins€¦ · Membranes - a closer look - Cellular lipid membranes are heterogeneous systems with a variety of lipids, cholesterol and proteins - permeable
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School on Biomolecular Simulations
Membranes & MembraneProteins
Vani VemparalaThe Institute of Mathematical Sciences
Chennai
November 13 2007JNCASR, Bangalore
www.elsomresearch.com/.../nanosomes.htm
Cellular Environment
cytoplasm
extracellular
http://learn.genetics.utah.edu/units/basics/cell/
Plasma membrane
no membrane → no cell → no life
- acts as a compartment, only fewmolecules thick (60-100 Å)- lipid molecules are added/removed, asthe cell dimension changes- can self-heal- held together byhydrophobic/noncovalent interactions- has a fluid-like structure with rapid lipiddiffusion-electrical potential across membranes : -60 mV- lipid molecules are synthesized in ER
endoplasmic reticulum
Membranes - a closer look
- Cellular lipid membranes are heterogeneous systems with a variety of lipids,cholesterol and proteins- permeable to non-polar molecules (O2, CO2) and small polar molecules likewater (osmosis); non-permeable to: ions, charged molecules (glucose),macromolecules (proteins)- membrane proteins can participate in cell recognition (through glycoproteins)- many different types of lipid molecules
Molecular Cell Biology, Fourth Edition W. H. FREEMAN, 2000
Membranes - Components
- membranes mostly contain lipids and proteins- membrane lipids contain hydrophobic and hydrophilic moieties- form barriers to free flow of charged species- ~30% of proteins are membrane proteins-~50% of current drug targets are membrane proteins
Lipid Structure
Hydrophilic head
Hydrophobic tail
Lipid molecules are amphipathic
Hydrophilic molecules readily dissolve in water (forming favourable electrostatic /hydrogen bond interactions)
Hydrophobic molecules are insoluble in water. Energetic cost minimized ifhydrophobic molecules cluster ( e.g., oil coalesces to form a drop when dispersed inwater)
Conflicting forces experienced by amphipathic molecules resolved in theformation of bilayer - energetically most favourable
polar
nonpolar
saturated unsaturated
cholesterol phospholipids
Lipids to Cells
Free edges with exposedhydrophobic tails
- Self-healing property of lipids
- Free edges are energetically expensive
- overriding principle: free edges shouldbe eliminated
Sealed compartments
- profound effect: formation of closedcompartmental structures
- Amphipathic nature oflipids is fundamental
Head groupHead group
PhosphatePhosphate
GlycerolGlycerol
Fatt
y ac
id c
hain
Fatt
y ac
id c
hain
Fatt
y ac
id c
hain
Fatt
y ac
id c
hain
zwitterioniczwitterionic
chargedcharged
Pola
rPo
lar
Non
-pol
arN
on-p
olarPhospholipid Structure
Typical head groups:PC-phosphotidylcholinePE-phosphotidyletanolaminePG-phosphotidylglycerolFatty acid chain:14(myristic)-22(docosahexaenoic)carbon-may contain double bonds(unsaturated)-mostly even number of carbons
Charged lipids: ~ 10%
Choline - phosphatidyl choline. (PC) Ethanolamine - phosphatidyl ethanolamine. (PE)
Serine - phosphatidyl serine (PS) Glycerol - phosphatidyl glycerol.(PG)
PC, PE - neutral (zwitter-ionic)PS, PG- charged
Lipid: Head Groups
Oleic acid: monounsaturated C18(18:1)
Stearic acid: saturated C18(18:0)
Palmitic acid: saturated C16(16:0)
Docasahexaenoic acid: saturated C22(22:6)
Fatty acid chains
lipids can have two fatty acid chains of unequal lengthone or more chains can be unsaturatedLipids can have a rich variety by varying: fatty acid chainlength, degree of saturation, polar head group etc.,
Lipid: Fatty Acid Chains
effect on cell membrane fluidity
http://cellbio.utmb.edu/cellbio/membrane_intro.htm
http://courses.cm.utexas.edu/jrobertus/ch339k/overheads-2/ch11_cholesterol.jpg
Cholesterol is one of the most abundant lipidmolecules
Regulates the fluid-like nature of membranes,hence affects membrane dynamics
most cells (animal) have ~ 20-50%cholesterol
Cholesterol
Cholesterol: Lipid Rafts
Heterogeinity of lipids (saturated/unsaturated) has lead to mosaic-domain models (liquid-liquid immiscibility)
Domains rich in ‘sphingolipids’ and ’cholesterol’ - lipid rafts
Role of Rafts proposed in function of trafficking and sorting newly formed lipids
Rafts implicated in diseases such as HIV, Alzheimer’s (pathogens may gain cellular entryby accessing lipid rafts)
Membranes: Fluid Nature
lateral diffusion
rotation
flip-flop
Fluidity: ease with which lipidmolecules move within plane ofmembrane
- depends on lipid composition,temperature
- regular packing leads to less fluidity;unsaturation increases fluidity
saturated unsaturated
Double bond
Membrane fluidity plays role in: cellsignalling, movements of newly formed lipidmolecules, cell division, cell fusion etc,
Membrane: Analysis
- average area/lipid
- membrane thickness
- electron density profile
- order parameters
- tilt angle of hydrocarbon chains
- pressure profiles
- permeation of various small molecules across membranes
- diffusion of lipid molecules
- surface tension across membranes
- electrostatic potential change
Membrane: Setup
- unlike proteins, no initial coordinates available
- make your own structures or look for existing bilayer patches
- hack into existing lipid topologies to build new ones
- CHARMM 27 force field has lipid topologies/parameter files
- VMD has membrane plugin (very limited)
POPE entry: topology file
Lipid: Coarse Graining
O2, C2, N2,benzene
Smallhydrophobicmolecules
H2O,ethanol
Smalluncharged
polarmolecules
Aminoacids
Largeunchargedmolecules
ions
Na+, Cl-
Membranes: Permeability
Extra cellular
Intra cellular
Specialized transport proteins are required
Membrane Proteins
- Genomics – Membrane Proteins constitute ca. 25% to 30% of allgenes- Membrane Proteins are implicated in many diseases: Diabetes,Parkinson’s, drug resistance (tumours & bacteria) …
- Membrane Proteins are major drug targets- ~50% of current drug targets are membrane proteins
Nobel Prize in Chemistry 2003
Trends Pharm Sci 22:23-26 (2001)
< 20 crystal structures knownKcsA KirBac1.1/3.1
Membrane Proteins
extra cellular domain
transmembrane domain
intra cellular domain
α-helices are most commonform in transmembrane domain
detergents used to separatemembrane proteins from
membrane
gating (~1 ms)
Filter
Pore
Gate
open closed
Ion Channels: Gating
Gating : stimulus-triggered
Stimulus: ligand, voltage, stress
Cavity
SelectivityFilter
Gate
Ion Channels: Selectivity
• Potassium selective -K+ radius = 1.33Å; Na+ radius = 0.95Å
Hydrophobic Mismatch
Thank You
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