Protein Folding experiments and theory

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1 Protein Folding experiments and theory

2 1, 2,and 3 Protein Structure Fig from Lehninger Biochemistry, 4 th ed.

3 The 3D structure is not encoded at the single aa level

4 Hydrogen Bonding Shared H atom between N, O; sometimes Cl, F H X bond aligned with unpaired electrons: strongly directional Intramolecular H-bond vs. with solvent water Figure 2-11 from Lehninger Biochemistry, 4 th Ed.

5 Electrostatic Bonds: Salt Bridges Unlike charges attract Coulombic interactions weak in polar solvent Competition between ion pairing and solvated charges Energetically unfavorable in hydrophobic interior Free energy predictable from coulomb theory

6 Ions are Happier Hydrated: Salt Dissolves in Water Figure 2-6 from Lehninger Biochemistry, 4 th Ed.

7 Hydrophobic Interactions: Entropy- Driven Main thermodynamic source of protein stability The water doesn t dislike grease, it just likes itself more Hydrogen-bonded clathrate cage: minimize surface area Hydrophobic effect maximizes entropy of the water: Strongly temperature-dependent

8 Water Forms a Transient, H-Bonded Lattice Water molecules are H-bond donors, acceptors; Form H-bonded lattice Maximize config. entropy by having many partners Non H-bonding solute in cavity; water lining cavity has low entropy, so minimize surface area

9 Hydrophobic effect sometimes called hydrophobic forces

10 Hydrophobic Effect is Entropy Driven Entropy plotted vs. surface area of cavity enclosing hydrophobic solute in water: smaller molecules require smaller cavity, reduce entropy less, are more soluble Upper panel aliphatic, lower panel aromatic Figure5-21 from Kyte

11 Hydrophobic Residues on the Inside Hydrophobic residues and heme are hidden from the outside; most ΔG stabilizing protein comes from hydrophobicity

12 Relation to thermodynamics H = Upot + pv G = H TS Δ G =ΔH TΔS Δ = 0 G RTln K eq P P B A = K = e eq P A P B ΔG 0 / RT K eq = equilibrium constant Boltzmann rules! kt B k = κ h e ΔG ΔG / RT k = rate constant

13 Christian B. Afinsen ( ): reversible folding of ribonuclease (Nobel Prize 1972)

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15

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17 The conformational search problem (Levinthal s paradox) consider only backbone torsional angles with 3 conformations/residue 100 aa s = conformations So, how can proteins fold at all? ϕ i

18 General protein folding pathwys?

19 The folding funnel solution the energy landscape is stratified its statistical characteristics depend on the distance to the native state Entropy

20 The folding funnel experimental reconstruction from folding kinetics of lysozyme

21 Multiple Intermediates in Lysozyme Folding Figure 6 from O. Bieri and T. Kiefhaber in Mechanisms of Protein Folding, 2 nd Ed. (R. H. Pain, Ed.)

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23

24 Spectroscopic Approaches Circular Dichroism General, insensitive, low resolution, slow (msec) Fluorescence Fast (psec), sensitive, low resolution, few fluorophores NMR High resolution, medium speed (msec) and sensitivity Mass spectroscopy Not fast, limited scope (H-D exchange), good resolution

25 Other Important Techniques H-D Exchange Measure with mass spec or NMR: molecular detail Calorimetry Gives thermodynamics, no structural info; slow Protein Engineering Replace individual residues and measure effects

26 Exceptions to the simple folding picture Chaperones Chaperones (GroEL, hsp70) enclose nascent protein, provide isolation to prevent aggregation before fold completed Figure 4-31b from Lehninger Biochemistry, 4 th ed.

27

28 Computational protein folding lattice models

29 conformations -> conformations -> Computational protein folding lattice models U folding sequence U non folding

30 Computational protein folding: off-lattice models (molecular dynamics, Monte Carlo simulations) simplified (Levitt & Warshel, 1975) or all-atom

31

32 MD simulations of protein folding - examples peptides small proteins van Gunsteren et al. Pande et al.

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