Hue Sun CHAN   Professor

B.Sc., University of Hong Kong, 1981
M.A., University of California at Berkeley, 1983
Ph.D., University of California at Berkeley, 1987
Postdoctoral Fellow, University of California at San Francisco (UCSF), 1987-89
Assistant Research Biophysicist, Assistant Adjunct Professor,
Associate Adjunct Professor
, UCSF, 1989-98
Associate Professor, University of Toronto, 1998-2003
Canada Research Chair, 2001-2010
Professor, University of Toronto, 2003-present


Teaching:
BCH340H -- Proteins: From Structure to Proteomics (Archive)
JBB2026H -- Protein Structure, Folding and Design (offered NOW: Current Fall '12 course outline)

Member of:
CIHR Training Program (at U. of Toronto) in Protein Folding and Interaction Dynamics: Principles & Diseases (Program Advisory Committee)
Editorial Board: Proteins: Structure, Function, and Bioinformatics


Medical Sciences Building, Room 5363
416-978-2697
chan@arrhenius.med.utoronto.ca

Theoretical and Computational Approaches to Protein Folding



Research Synopsis
 



Moat Landscape, to illustrate how a protein could have a fast-folding throughway process (A), in parallel with a slow-folding process (B) involving a kinetic trap.

From Levinthal to pathways to funnels, Nature Structural Biology, Volume 4, No. 1, January 1997.




Current Research Group Members

Research Group Pictures

U. of Toronto pictures


Biophysics in Canada:
Links to other Canadian biophysics groups (kindly provided by Andrew Rutenberg)


Protein folding is a physico-chemical process. Our overall research goal is to elucidate its underlying energetics. To this end, we have been developing a number of proteinlike heteropolymer models with coarse-grained interactions and simplified representations of chain geometries. The rationale is to capture the essential physics and allow for a broad coverage of the conformational space -- in some cases also the model sequence space -- at a level of relative mathematical rigor currently not achievable in higher-resolution protein models. These methods have been used to gain physical insight into general features of protein folding, including the effects of temperature and denaturant dependences of hydrophobic interactions on native stability and folding/unfolding kinetics. Our effort to decipher the interactions in real proteins entails applying exhaustive enumeration (i.e., accounting for all possible sequences and conformations in a given model), Monte Carlo sampling and molecular dynamics to analyze how the mathematical form of a model protein's potential function affects sequence degeneracy, structural encodability or designability, calorimetric cooperativity and other thermodynamic and kinetic properties of model proteins. The polymer-physics-based sequence-structure mappings afforded by these approaches are also utilized to develop theories of evolutionary landscapes.

To better understand protein energetics, a closely related area of interest is statistical mechanical theories and atomic simulation of aqueous solvation. In particular, hydrophobicity is of central importance to a broad range of biomolecular phenomena such as formation of biological membranes, binding, and protein folding. We seek a more detailed description of fundamental hydrophobic interactions by simulating potentials of mean force among nonpolar solutes in molecular models of water. This line of inquiry has led to discoveries that include a dramatic non-monotonic spatial dependence of the heat capacity effect associated with bringing together a pair of nonpolar solutes in water, and the observation that the thermodynamic signatures of the free energy barrier to the partial desolvation of two small nonpolar solutes have signs opposite to desolvation itself. These unexpected features have far-reaching implications on the balance of forces in protein folding, and are being further pursued.
 


Selected Publications
Polycation-π Interactions are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family. J. Song, S. C. Ng, P. Tompa, K. A. W. Lee & H. S. Chan, PLoS Comput. Biol. 9(9):e1003239 (2013).

Transition Paths, Diffusive Processes, and Preequilibria of Protein Folding. Z. Zhang & H. S. Chan, Proc. Natl. Acad. Sci. USA 109:20919-20924 (2012).

Evolutionary Dynamics on Protein Bi-Stability Landscapes can Potentially Resolve Adaptive Conflicts. T. Sikosek, E. Bornberg-Bauer & H. S. Chan, PLoS Comput. Biol. 8(9):e1002659 (2012).

Escape from Adaptive Conflict Follows from Weak Functional Trade-Offs and Mutational Robustness. T. Sikosek, H. S. Chan & E. Bornberg-Bauer, Proc. Natl. Acad. Sci. USA 109:14888-14893 (2012).

Cooperativity, Local-Nonlocal Coupling, and Nonnative Interactions: Principles of Protein Folding from Coarse-Grained Models. H. S. Chan, Z. Zhang, S. Wallin & Z. Liu, Annu. Rev. Phys. Chem. 62:301-326 (2011).

Action at Hooked or Twisted-Hooked DNA Juxtapositions Rationalizes Unlinking Preference of Type-2 Topoisomerases. Z. Liu, L. Zechiedrich & H. S. Chan, J. Mol. Biol. 400:963-982 (2010).

Competition Between Native Topology and Nonnative Interactions in Simple and Complex Folding Kinetics of Natural and Designed Proteins. Z. Zhang & H. S. Chan, Proc. Natl. Acad. Sci. USA 107:2920-2925 (2010).

Desolvation Barrier Effects are a Likely Contributor to the Remarkable Diversity in the Folding Rates of Small Proteins. A. Ferguson, Z. Liu & H. S. Chan, J. Mol. Biol. 389:619-636 (2009).

Theoretical and Experimental Demonstration of the Importance of Specific Nonnative Interactions in Protein Folding. A. Zarrine-Afsar, S. Wallin, A. M. Neculai, P. Neudecker, P. L. Howell, A. R. Davidson & H. S. Chan, Proc. Natl. Acad. Sci. USA 105:9999-10004 (2008).

Polyelectrostatic Interactions of Disordered Ligands Suggest a Physical Basis for Ultrasensitivity. M. Borg, T. Mittag, T. Pawson, M. Tyers, J. D. Forman-Kay & H. S. Chan, Proc. Natl. Acad. Sci. USA 104:9650-9655 (2007).

Hydrophobic Association of α-Helices, Steric Dewetting and Enthalpic Barriers to Protein Folding. J. L. MacCallum, M. Sabaye Moghaddam, H. S. Chan & D. P. Tieleman, Proc. Natl. Acad. Sci. USA 104:6206-6210 (2007).

Topological Information Embodied in Local Juxtaposition Geometry Provides a Statistical Mechanical Basis for Unknotting by Type-2 DNA Topoisomerases. Z. Liu, J. K. Mann, E. L. Zechiedrich & H. S. Chan, J. Mol. Biol. 361:268-285 (2006).

Desolvation is a Likely Origin of Robust Enthalpic Barriers to Protein Folding. Z. Liu & H. S. Chan, J. Mol. Biol. 349:872-889 (2005).

Temperature Dependence of Three-Body Hydrophobic Interactions: Potential of Mean Force, Enthalpy, Entropy, Heat Capacity, and Nonadditivity. M. Sabaye Moghaddam, S. Shimizu & H. S. Chan, J. Am. Chem. Soc. 127:303-316 (2005).

Sparsely Populated Folding Intermediates of the Fyn SH3 Domain: Matching Native-Centric Essential Dynamics and Experiment. J. E. Ollerenshaw, H. Kaya, H. S. Chan & L. E. Kay, Proc. Natl. Acad. Sci. USA 101:14748-14753 (2004).

Cooperativity Principles in Protein Folding. H. S. Chan, S. Shimizu & H. Kaya, Methods Enzymol. 380:350-379 (2004).

Origins of Chevron Rollovers in Non-Two-State Protein Folding Kinetics. H. Kaya & H. S. Chan, Phys. Rev. Lett. 90:258104 (2003).

Recombinatoric Exploration of Novel Folded Structures: A Heteropolymer-Based Model of Protein Evolutionary Landscapes. Y. Cui, W. H. Wong, E. Bornberg-Bauer & H. S. Chan, Proc. Natl Acad. Sci. USA 99:809-814 (2002).

Conformational Propagation with Prion-like Characteristics in a Simple Model of Protein Folding. P. M. Harrison, H. S. Chan, S. B. Prusiner & F. E. Cohen, Protein Sci. 10:819-835 (2001).

Folding Alphabets. H. S. Chan, Nature Struct. Biol. 6:994-996 (1999).

Energetic Components of Cooperative Protein Folding. H. Kaya & H. S. Chan, Phys. Rev. Lett. 85:4823-4826 (2010).

Modeling Evolutionary Landscapes: Mutational Stability, Topology and Superfunnels in Sequence Space. E. Bornberg-Bauer & H. S. Chan, Proc. Natl. Acad. Sci. USA 96:10689-10694 (1999).

Protein Folding: Matching Speed and Locality. H. S. Chan, Nature 392:761-763 (1998).

Protein Folding in the Landscape Perspective: Chevron Plots and Non-Arrhenius Kinetics. H. S. Chan & K. A. Dill, Proteins: Struct. Funct. Genet. 30:2-33 (1998).

From Levinthal to Pathways to Funnels. K. A. Dill & H. S. Chan, Nature Struct. Biol. 4:10-19 (1997).
  Click here for an extended list of publications and electronic reprints.

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