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Entropic and Enthalpic Barriers in Cooperative Protein Folding

IMA, January 17, 2008. Entropic and Enthalpic Barriers in Cooperative Protein Folding. Departments of Biochemistry, and of Molecular Genetics University of Toronto, Ontario M5S 1A8 Canada http://biochemistry.utoronto.ca/chan/bch.html. Hue Sun C HAN. Cooperative Folding:.

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Entropic and Enthalpic Barriers in Cooperative Protein Folding

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  1. IMA, January 17, 2008 Entropic and Enthalpic Barriers in Cooperative Protein Folding Departments of Biochemistry, and of Molecular Genetics University of Toronto, Ontario M5S 1A8 Canada http://biochemistry.utoronto.ca/chan/bch.html Hue Sun CHAN

  2. Cooperative Folding: What do we know from experiments?

  3. How does the calorimetric criterion work? bimodal cooperative folding unimodal noncooperative folding

  4. Kinetic manifestation of folding cooperativity: linear chevron plots Data from Jackson et al., Biochemistry 32:11270 (1993) Linear folding and unfolding arms imply a linear relationship between log(folding/unfolding rate) and equilibrium stability chevron rollover is indicative of less cooperative or noncooperative folding

  5. Do we understand the Physics of Generic Protein Properties? Most current coarse-grained protein chain models do not satisfy experimental cooperativity criteria Chan et al., Methods Enzymol (2004)

  6. Continuum CaGo Models CI2 Clementi et al., JMB (2000); Koga & Takada, JMB (2001); Kaya & Chan, JMB (2003) Native-centric local and non-bonded interactions Langevin dynamics Thermodynamically quite cooperative

  7. Go-model chevron plots have significant chevron rollovers, implying that in many cases Go models are less cooperative than the real proteins they aim to mimick Theory Experiment Kaya & Chan, JMB (2003) Jackson & Fersht, Biochemistry (1991)

  8. Even with native biases, pairwise additive coarse-grained interactions do not account for cooperative folding Better Mesoscopic Principles?

  9. ‘Many-body’ interactions needed to account for folding cooperativity A hypothesized cooperative interplay between favorable nonlocal interactions and local conformational preferences (local-nonlocal coupling) Kaya & Chan, Proteins (2003)

  10. Testing the local-nonlocal coupling idea by lattice models a < 1, attentuation factor Kaya & Chan, Proteins (2003)

  11. Native Topology (Contact Pattern) Dependent Folding Rates Plot from Plaxco et al. Biochemistry (2000) Plaxco, Simons & Baker, JMB (1998) Can protein chain models capture this trend?

  12. Many-body interactions in the form of local-nonlocal coupling rationalize topology-dependent folding rates Kaya & Chan, Proteins (2003); Chan et al., Methods Enzymol (2004)

  13. Our theoretical perspective was corroborated by experiments: Cooperativity is likely an evolutionarily selected trait; cooperativity is not a corollary of a protein’s ability to fold Top7, 1qys (93aa) Kuhlman et al., Science (2003) experiment theory Scalley-Kim & Baker, JMB (2004); Watters et al., Cell (2007) Kaya & Chan, Proteins (2003)

  14. Kaya & Chan, Proteins (2003)

  15. Folding Barriers entropic & enthalpic components

  16. Entropic Barriers: Role of conformational entropic barriers in native topology-dependent folding rates Wallin & Chan, J Phys Condens Matt (2006)

  17. ‘Transition state’ as conformations around the Q barrier Q = fractional number of native contacts Transition-state ensembles: 1div 1wit 1imq 1pgb Wallin & Chan, J Phys Condens Matt (2006)

  18. … found some correlation between model and experimental folding rates, suggesting that the model captures part of the physics Wallin & Chan, J Phys Condens Matt (2006); cf. Koga & Takada, JMB (2001)

  19. Entropic barriers: The topology-folding rate relationship is likely dominated by conformational entropy effect Wallin & Chan, J Phys Condens Matt (2006)

  20. Enthalpic barriers: non-Arrhenius folding rates, positive unfoled-to-transition state enthalpy changes at some temperatures Does this mean that the folding landscape is not funnel-like? lower temperature

  21. Thermodynamic Signatures of Protein Folding Kinetics CI2 “reaction profiles” DCp DH enthalpic barrier 25 °C DS 25 °C

  22. Desolvation is a likely origin of robust enthalpic barriers to protein folding Liu & Chan, JMB (2005)

  23. Desolvation barriers enhance folding/unfolding cooperativity increasing height of pairwise desolvation barrier leads to … Higher overall free energy barrier CI2 CI2 more linear chevron plots less native fluctuation Liu & Chan, JMB (2005); Phys Biol (2005); cf. Cheung et al., PNAS (2002); Kaya & Chan, JMB (2003)

  24. Desolvation barrier effects are a likely contributor to the remarkable diversity in the folding rates of small proteins simulated folding rates span ~4.5 orders of magnitude simulated folding rates span ~1.5 orders of magnitude A. Ferguson, Z. Liu & H.S. Chan (2007)

  25. …but pairwise desolvation barriers alone are insufficient to account for the thermodynamic signatures of cooperative folding

  26. x Typically, Unfolded-to-Transition-State heat capacity change is negative for protein folding, but … for the association of small nonpolar solutes in water, heat capacity change is positive around the desolvation free energy barrier. Length-scale dependence provides a possible probe for cooperativity? TIP4P water model from DG at 8 temperatures • DCPhighly non-monotonic • Not well predicted by surface areas Shimizu & Chan, JACS (2001)

  27. x Hydrophobic interactions among smallhydrophobic solutes: Robust D CP > 0at the desolvation free energy barrier 2-body r Xe 3-body CH4 r / nm Moghaddam, Shimizu & Chan, JACS (2005) Paschek, J Chem Phys120:6674 (2004)

  28. Enthalpy-Entropy Compensation at Desolvation temperature dependence of the potential of mean force (PMF) Enthalpic barrier can be significantly higher than the desolvation free energy barrier Moghaddam, Shimizu & Chan, JACS (2005); Liu & Chan, JMB (2005)

  29. a-Helix association in water as a model for rate-limiting events in protein folding A pair of 20-residue poly-alanine or poly-leucine helices ~3,800 water molecules Simulated constant-pressure free energy of association (potential of mean force, PMF) at five temperatures MacCallum, Moghaddam, Chan & Tieleman, PNAS (2007)

  30. Enthalpic desolvation barriers of ~ 50 kJ/mol comparable to that of protein folding Dramatic enthalpy-entropy compensation at the desolvation step leading to low or non-existent free energy barriers At 25 deg C, Enthalpic folding barrier height for CI2 is ~ 30kJ/mol(Oliveberg et al., 1995) CspB is ~ 32kJ/mol(Schindler & Schmid, 1996) MacCallum, Moghaddam, Chan & Tieleman, PNAS (2007)

  31. Enthalpic barriers caused by steric dewetting MacCallum, Moghaddam, Chan & Tieleman, PNAS (2007)

  32. Recap.: Folding cooperativity implies ‘near-Levinthal’ funnels Enthalpic barriers can be consistent with funnel-like folding landscapes ?

  33. Co-workers University of Toronto University of Toronto Prof. Julie D. Forman-Kay Artem Badasyan Allison Ferguson Prof. Regis Pomes University of Calgary Mikael Borg Huseyin Kaya Michael Knott Zhirong Liu Maria Sabaye Moghaddam Seishi Shimizu Stefan Wallin Prof. D. Peter Tieleman Justin MacCallum University of Muenster Prof. Erich Bornberg-Bauer David Vernazobres Richard Wroe

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