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PHYS5530M Physics of Biological Systems > Phase Separation in Biological Systems > Flashcards

Phase Separation in Biological Systems Flashcards

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1
Q

Compartmentalisation of Cells

A
  • in eukaryotic cells have many compartments / organelles with specfic functions and provide spatiotemparal control over cell materials / metabolic pathways etc.
  • most organelles have a membrane boundary but there are also many membraneless organelles
  • these are supramolecular assemblies of proteins and RNA molecules and typically form liquid droplets or hydrogels
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2
Q

Biophysical Assays of Membraneless Compartments

A

-established liquid nature of some membraneless compartments

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3
Q

Protein Granule Model of Membraneless Compartments

A
  • protein granules are a good model of liquid membraneless compartments
  • molecules diffuse freely within protein granule
  • two protein granules can fuse into one
  • one protein granule can bud of from another
  • spherical shape from surface tension
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4
Q

Liquid-Liquid Phase Separation

Description

A
  • entropy of mixing drives spontaneous mixing of components

- there is a predicted entropy increase with mixing and this drive to spontaneous mixing is always there

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5
Q

Liquid-Liquid Phase Separation

Volume Fractions

A 
φ1 = volume fraction of component 1
φ2 = volume fraction of component 2

φ1 + φ2 = 1

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6
Q

Liquid-Liquid Phase Separation

Concentrations

A 
φ = volume fraction
υ = molecular volume
c = concentration

c = φ/υ

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7
Q

Liquid-Liquid Phase Separation
De-Mixing
Description

A

-repulsion between components can lead to de-mixing
-two co-existing phases with volume fractions φ1=φs & φ1=φd
-there is no net-flux of molecules across the interface since:
μ1(φs) = μ1(φd)

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8
Q

Liquid-Liquid Phase Separation
De-Mixing
Free Energy of Mixing

A

F = E - T Smix

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9
Q

Liquid-Liquid Phase Separation
De-Mixing
Interaction Energy

A

E = χ12 V φ1 (1 - φ1)

-where χ12 is the FLory interaction parameter

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10
Q

Liquid-Liquid Phase Separation
De-Mixing
Chemical Potential

A

μ1 = υ1 / V dF/dφ1

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11
Q

Liquid-Liquid Phase Separation Surface Tension

Overview

A
  • entails coarsening of the disperse phase (droplets)
  • owing to the Laplace pressure one large droplet is favourable over many small droplets
  • droplets may coarsen by fusion or Ostwald ripening
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12
Q

Liquid-Liquid Phase Separation Surface Tension

Laplace Pressure

A

ΔP = Pin - Pout = 2γ/R

-where γ is the surface tension

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13
Q

Liquid-Liquid Phase Separation Surface Tension

Ostwald Ripening

A

-droplets leave smaller droplet in preference of larger one

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14
Q

2D Compartments

Overview

A
  • compartmentalisation also occurs in 2D

- e.g. in lipid bilayer membranes and polymer brushes

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15
Q

2D Compartments

Lipid Bilayer Membranes

A
  • microdomains within lipid membranes

- same driving mechanisms as 3D

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16
Q

2D Compartments

Polymer Brushes

A
  • glycocalyces may phase separate in 2D

- potentially driven by cross-linking of polysaccaride scaffold

17
Q

2D Compartments

Perineural Nets

A
  • HA brushes as invitro model of perineural nets

- demonstrate cross-linking by proteins can recapitulate granular and reticular phases

18
Q

2D Compartments

Phases

A
  • basic priniples are the same as for 3D
  • granular and reticular phases represent polymer-rich phase being the dispose and continuous phase respectively
  • a change to substrate provides extra effects (e.g. microphase separation if anchors are immobile and cannot move in plane)
19
Q

Functions of Membraneless Compartments

List

A
  • concentration of biochemical reactions
  • sequestering harmful components
  • storage of biomolecules
  • sieving
  • signal amplitude and noise reduction
20
Q

Functions of Membraneless Compartments

Concentration of Biochemical Reactions

A
  • benefits from concentrated liquid phase where reactants can easily meet
  • composition may be dsitinct from surrounding continuous phase leading to different reactions
21
Q

Functions of Membraneless Compartments

Sequestering Harmful Components

A

-protein aggregates in disease are harmful but could be the initial rescue mechanism of cells to sequester more toxic protein oligomers

22
Q

Functions of Membraneless Compartments

Sieving

A

-nuclear pore permeability barrier controls biomolecule transport between the nucleus and cytoplasm

23
Q

Functions of Membraneless Compartments

Signal Amplitude and Noise Reduction

A
  • signal pathways amplified by conecntrating receptors in membrane micro domains
  • liquid-liquid phase separation decrease protein concentration fluctuations thereby reducing noise in signalling pathways
24
Q

Phase Separation as a Mechanism to Reduce Noise in Cells

A
  • proteins are produced in the cell cytoplasm by ribosomes, there are many ribosomes but only a small number will be producing any particular protein at any given time
  • this can lead to large variations in protein concentration across the cell but for biochemical reactions it is useful to reduce theis noise and acheive a more uniform concentration
  • liquid-liquid phase separtion provides a mechanism to reduce this noise by the creation of two phases, the dilute phase of low protein concentration and the dispere phase of high protein concetration
  • when total protein concentration changes, the size and number of the droplets changes but the concentrations in both the continuous and disperse phases remains constant
25
Q

Does phase separtion theory hold in non-equilbirium conditions in real cells?

A
  • the important factors are protein diffusion time and protien turnover time
  • if diffusion time is < < turn over time the cell is essentially at equilibrium all the time
  • good agreement with experiment
26
Q

Dynamics of Phase Separation

Using Phase Separation in Cells

A

-to harness phase separation, cells need to control kinetics of phase separation and droplet size

27
Q

Dynamics of Phase Separation

Initiation of New Droplet

A

-may require a nucleation event (as in crystlisation)

28
Q

Dynamics of Phase Separation

Nucleation

A
  • homogeneous nucleation, spontaneous nucleatoin via random fluctuatoin
  • heterogeneous nucleation, at dedicated sites have regions which promote nucleation to help control where and how many components form
29
Q

Dynamics of Phase Separation

Fusion

A
  • spontaneous fusion of droplets may be avoided by:
  • -physical separation e.g. entrapment in the cytoskeletal network
  • -surface active molecules (e.g. polymer prush on chromosomes), molecules are essentially designed to repel each other
30
Q

What are the requirements on proteins to phase separate?

A
  • proteins known to drive phase separation have distinct features:
  • -large number of interaction motifs (polyvalency)
  • -individual interactions are weak (low affinity, few kbT)
  • -intrinsically disordered linkers that separate interaction motifs (conformational flexibility)
31
Q

Importance of Linker Properties for Phase Transition

A
  • simulations highlight the importance of linker properties for phase transition:
  • -flexible linkers promote phase transition and gelation
  • -bulky linkers promote gelling without phase transition
32
Q

Physics Challenges of Phase Separation

A
  • important aspects of phase separation are still poorlt understood
  • phase separation in multi component, multi compartment systems is complex
  • same for phase separation in active cells
33
Q

Experimental Challenges of Phase Separation

A
  • compositional complexity of cytoplasm makes system control and quantitative analysis challenging
  • combination of well-defined reconsitiuted in-vitro models and complex real cell models will be required to generate quantitative models of underpinning mechanisms and validate biological relevance
34
Q

Phase Separation and Superselectivity

A
  • polyvalency, low affinity and conformational flexibility are key ingredients for protein phase separation
  • these are the same criteria as for superselectivity
  • could there be a connection?

PHYS5530M Physics of Biological Systems (12 decks)

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