Graduate Biophysics Course · BPH 714
The Biophysics of Cellular Organelles
The eukaryotic cell as a federation of physically distinct compartments — where thermodynamics, membrane mechanics, and (occasionally) quantum coherence conspire to sustain life far from equilibrium.
About This Course
A eukaryotic cell is not a bag of chemistry. It is a spatial organisation of chemistry — a set of compartments that maintain, against the universal pressure of the second law, distinguishable internal states. The nucleus holds a different pH than the cytosol; the mitochondrion holds a proton gradient that a physicist would recognise as a battery; the lysosome holds enzymes whose kinetics are tuned to one compartment and catastrophic in another. This course asks, throughout, a single question: what physics makes a compartment worth the cost of building it?
Eight modules move from foundational thermodynamics of compartmentalisation, through the Canham–Helfrich elasticity of bilayers, through each of the canonical membrane-bounded organelles, into the phase-separated membraneless compartments that the past two decades have added to the catalogue, and finally to the inter-organelle contact network that integrates them into a single living cell.
Featured Lecture — Tom Rapoport (Harvard / HHMI)
Tom Rapoport’s iBiology lecture on Organelle Biosynthesis and Protein Sorting is the canonical introduction to how the cell builds and populates its compartments — cotranslational translocation, signal peptides, the Sec61 channel, SRP targeting. This is the mechanistic scaffolding on which the biophysics of the rest of the course hangs.
iBiology · Harvard Medical School / HHMI. Watch first; return to it in Module 3 where the biophysics of the SRP/Sec61 targeting reaction is derived.
Key Equations
Canham-Helfrich Energy
\( \mathcal{H} = \int dA \left[\tfrac{\kappa}{2}(2H-C_0)^2 + \bar\kappa K + \sigma\right] \)
Membrane Fluctuation Spectrum
\( \langle|h_{\mathbf{q}}|^2\rangle = \dfrac{k_B T}{\kappa q^4 + \sigma q^2} \)
Proton-Motive Force
\( \Delta\tilde\mu_{H^+}/F = \Delta\psi - (2.303\,RT/F)\,\Delta\mathrm{pH} \)
Marcus Rate
\( k_{ET} \propto |H_{DA}|^2 \exp\!\left[-\dfrac{(\Delta G^\circ + \lambda)^2}{4\lambda k_B T}\right] \)
Flory-Huggins Free Energy
\( f/k_B T = \dfrac{\phi}{N}\ln\phi + (1-\phi)\ln(1-\phi) + \chi\phi(1-\phi) \)
Cathepsin pKa Activity
\( f_{active}(\mathrm{pH}) = \dfrac{1}{1 + 10^{\mathrm{pH}-\mathrm{pK_a}}} \)
Eight Modules
M0
Why Compartmentalize?
Information, concentration, chemical exclusion, regulatory leverage; the thermodynamic cost of maintaining distinguishable compartments against the second law.
M1
Membrane Biophysics
Canham-Helfrich elastic energy, bending rigidity, Gaussian curvature, spontaneous curvature, fluctuation spectrum, Helfrich 1973 crossover scale.
M2
The Nucleus
Nuclear pore complex, FG-nucleoporin selective phase, importin-beta/RanGTP cycle, chromatin as a polymer, fractal globule, loop extrusion.
M3
Endoplasmic Reticulum
Cotranslational translocation, Sec61, signal peptides, folding in the funnel, calnexin cycle, ERAD, UPR as a control loop. With Tom Rapoport lecture.
M4
Mitochondria
Chemiosmotic coupling, proton-motive force, F1F0 ATP synthase stoichiometry, cristae geometric optimisation, Marcus electron transfer in the ETC.
M5
Lysosomes & Peroxisomes
V-ATPase acidification, pKa engineering of cathepsins, lysosomal membrane permeabilization, lysosomal storage disorders, peroxisome biogenesis.
M6
Membraneless Organelles
Flory-Huggins demixing, multivalent IDPs, nucleoli, stress granules, ALS-linked liquid-to-solid transitions of FUS and TDP-43.
M7
The Integrated Cell
Membrane contact sites (MAMs), ER-mitochondria tethering, inter-organelle lipid transfer, organelle positioning, compartments as a federated graph.
Cross-Links
Cell Physiology,Mitochondria,Biochemistry,Cytoskeleton,Biophysics,Molecular Biology.
Foundational References
- [1] Helfrich, W. (1973). Elastic properties of lipid bilayers. Z. Naturforsch. C, 28, 693–703.
- [2] Mitchell, P. (1961). Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature, 191, 144–148.
- [3] Marcus, R. A. & Sutin, N. (1985). Electron transfers in chemistry and biology. BBA, 811, 265–322.
- [4] Frey, S. & Görlich, D. (2007). A saturated FG-repeat hydrogel can reproduce the permeability properties of NPCs. Cell, 130, 512–523.
- [5] Hyman, A. A., Weber, C. A. & Jülicher, F. (2014). Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol., 30, 39–58.
- [6] Lane, N. & Martin, W. (2010). The energetics of genome complexity. Nature, 467, 929–934.
- [7] Walter, P. & Ron, D. (2011). The unfolded protein response. Science, 334, 1081–1086.
- [8] Scorrano, L. et al. (2019). Coming together to define membrane contact sites. Nat. Commun., 10, 1287.