IMA, January 17, 2008 Entropic and Enthalpic Barriers

IMA, January 17, 2008 Entropic and Enthalpic Barriers

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

How does the calorimetric criterion work? bimodal cooperati ve folding unimodal noncooperat ive folding 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 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) Continuum C Go Models CI 2 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

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)

Even with native biases, pairwise additive coarse-grained interactions do not account for cooperative folding Better Mesoscopic Principles? 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 Testing the local-nonlocal coupling idea by lattice models a < 1, attentuation factor Kaya & Chan, Proteins (2003) Native Topology (Contact Pattern) Dependent Folding Rates

Plaxco, Simons & Baker, JMB (1998) Plot from Plaxco et al. Biochemistry (2000) Can protein chain models capture this trend? 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)

Our theoretical perspective was corroborated by experiments: Cooperativity is likely an evolutionarily selected trait; cooperativity is not a corollary of a proteins ability to fold theor y Kaya & Chan, Proteins (2003) Top7, 1qys

(93aa) Kuhlman et al., Science (2003) experime nt Scalley-Kim & Baker, JMB (2004); Watters et al., Cell (2007) Kaya & Chan, Proteins (2003) Folding

Barriers entropic & enthalpic compone Entropic Barriers: Role of conformational entropic barriers in native topology-dependent folding rates Wallin & Chan, J Phys Condens Matt

(2006) Transition state as conformations around the Q barrier Q = fractional number of native contacts Transition-state ensembles: 1di v

1pg b 1imq 1wit Wallin & Chan, J Phys Condens Matt (2006) 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); JMB (2001) cf. Koga & Takada, Entropic barriers: The topologyfolding rate relationship is likely dominated by conformation

al entropy effect Wallin & Chan, J Phys Condens Matt (2006) Enthalpic barriers: non-Arrhenius folding rates, positive unfoledto-transition state enthalpy changes at some temperatures Does this mean that the folding

landscape is not funnel-like? lower temperature Thermodynamic Signatures of Protein Folding Kinetics CI2 reaction profiles Cp H

enthalpic barrier 25 C S 25 C Desolvation is a likely origin of robust enthalpic barriers to protein folding Liu & Chan, JMB

(2005) 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) Desolvatio n barrier effects are a likely contributo

r to the remarkabl e diversity in the folding rates of 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) but pairwise desolvation barriers alone are insufficient to account for the thermodynamic signatures of cooperative folding 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 G at 8 temperatures CP highly non-monotonic Not well predicted by surface areas Shimizu & Chan, JACS (2001) Hydrophobic interactions among small hydrophobic solutes:

Robust CP > 0 at the desolvation free energy barrier CH4 2-body Xe r 3-body Moghaddam, Shimizu & Chan, JACS (2005)

rn m 120:6674 (2004) Paschek, J Chem Phys 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) Helix association in water as a model for rate-limiting events in protein folding A pair of 20residue poly-alanine or poly-leucine helices ~3,800 water molecules

Simulated constantpressure free energy of MacCallum, Moghaddam, Chan & Tieleman, PNAS (2007) association 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)

Enthalpic barriers caused by steric dewetting MacCallum, Moghaddam, Chan & Tieleman, PNAS (2007) Recap .: Folding cooperativit

y implies nearLevinthal funnels Enthalpic barriers can be consistent with funnel-like ? Coworkers University of Toronto

Artem Badasyan Allison Ferguson Mikael Borg Huseyin Kaya Michael Knott Zhirong Liu University of Toronto Prof. Julie D. Forman-Kay Prof. Regis Pomes University of Calgary Prof. D. Peter

Tieleman Justin MacCallum University of Muenster Maria Sabaye Moghaddam Prof. Erich BornbergBauer Seishi Shimizu David Vernazobres

Stefan Wallin Richard Wroe

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