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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
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Medical
Sciences Building, Room 5363
416-978-2697
chan@arrhenius.med.utoronto.ca |
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Theoretical and Computational
Approaches to Protein Folding
Research Synopsis
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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.
Research
Group Pictures
U. of
Toronto pictures
Biophysics in Canada:
Links to
other Canadian biophysics groups
(kindly provided by Andrew Rutenberg)
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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.
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Selected Publications
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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). |
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Click
here for an extended list of publications
and electronic reprints.
Lectures
and seminars
Journal
cover images
Meetings
organized |
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