Hue Sun Chan

Hue Sun Chan was born and raised in Hong Kong. Upon completing his undergraduate degree in physics there, he pursued graduate study in theoretical particle physics at UC Berkeley, specializing in regularization of quantum field theories. After receiving his PhD in 1987, he joined Ken Dill’s research group at UCSF, first as a postdoctoral fellow then as an adjunct faculty, and shifted his research interest to protein biophysics. As one of a few researchers who pioneered theoretical studies of protein folding in the late 1980s, Chan has made seminal contributions during his UCSF years. These include discovering that secondary-structure-like local order can be enhanced by global conformational compactness, developing simple exact lattice protein models such as the HP model that have been widely applied, characterizing the role of kinetic traps and their implications on the folding energy landscape, and coauthoring several influential reviews on folding. In 1998, he left San Francisco to take up his present appointment.

After arriving in Toronto, Chan turned his attention to the physical origins of folding cooperativity. His research interests have also been broadened to include thermodynamics of solvent-mediated interactions, protein evolution, protein interactions involving intrinsically disordered proteins, and DNA topology. He has published more than 155 research papers, which have received a total of more than 20,000 citations. He is an editorial board member of Proteins: Structure, Function & Bioinformatics.

Theoretical and Computational Investigations of Protein Folding, Interactions, and Evolution.

Protein folding and interactions are physico-chemical processes. Our group’s overall research goal is to elucidate their underlying energetics. To this end, a main emphasis of our effort is to develop proteinlike heteropolymer models with coarse-grained interactions and simplified representations of chain geometries. The rationale of these approaches is to capture the essential physics and at the same time allow for a broad coverage of the protein conformational space — and also a broad coverage of the sequence space for evolutionary studies — that is not readily achievable currently in higher-resolution models.

Molecular dynamics simulations using common atomic forcefields and explicit water models are used in our work as well, especially for deciphering subtle properties of solvent-mediated interactions. Various combinations of coarse-grained and atomic methods are being used to gain physical insights into general principles of folding, protein interactions, and evolution. The topics we address including folding cooperativity, origin of enthalpic and volumetric folding barriers, nonnative effects in folding, formation of functional and disease-causing dynamic, “fuzzy” complexes involving intrinsically disordered proteins, and conformational switching in protein evolution. Some of these efforts are highlighted below.

Cooperativity and nonnative interactions in folding

The Levinthal paradox of protein folding is commonly perceived as a statement about the impossibility of folding by a completely random conformational search. Often missed in such narratives is that the question raised by Levinthal was in response to the experimental discovery of two-state, switch-like cooperative folding by calorimetry in the late 1960s, rather than to the issue of conformational search per se. Two-state folding is expected to serve biological functions such as avoidance of aggregation. Folding cooperativity likely emerges from a coupling between local structural preferences and nonlocal packing interactions. To elucidate this local-nonlocal coupling mechanism and other folding properties, we develop native-centric as well as “hybrid” models in which nonnative effects are treated perturbatively. Many-body interactions, hydrogen bonding, sidechain packing and solvation are now being examined for their impact on folding cooperativity.

Intrinsically disordered proteins

While many proteins function in their folded states, it is now clear that intrinsically disordered proteins (IDPs) perform critical functions in transcription, translation and cell cycle regulation. Altering the functions of these IDPs can lead to cancer and other diseases. Molecular recognition by IDPs often involves target-induced folding. However, certain IDPs interact with other proteins without coupled folding-binding. Those cases entail dynamic, “fuzzy” complexes in which the bound IDPs remain largely disordered. In collaboration with experimentalist colleagues, we are developing biophysical models of IDP conformational ensembles. A main focus of our effort is to decipher the role of multisite electrostatic and aromatic interactions in IDP function and malfunction.

Atomic simulations of solvent-mediated interactions

As part of our effort to understand protein energetics, we conduct atomic simulations of aqueous solvation. Comparisons between theory and experiment indicate a prominent role of desolvation barriers in cooperative folding. Desolvation effects are key to resolving an apparent inconsistency between experimentally observed enthalpic barriers and the funnel picture of folding. They also provide novel insights into volumetric barriers to folding. Results from these atomic studies — which are not always obvious a priori — are being used to build physically more accurate coarse-grained models.

Biophysical models of protein evolution

The study of protein evolution requires a model of the mapping between amino acid sequences and the conformational ensembles they encode. Because of their computational tractability, lattice models with biophysics-based interaction schemes are useful for addressing large-scale evolution across many different protein folds. Together with collaborators, we have applied this approach to several fundamental aspects of protein evolution. Our effort has led to the recognition that neutral nets of globular proteins are likely organized as superfunnels, and that sequence-space topology or mutational robustness can have significant impact on evolutionary population and thus can help resolve adaptive conflict.

Mathematical basis of type-2 topoisomerase action

Type-2 topoisomerases (topoIIs) are enzymes that unknot and decatenate DNA circles and reduce the variance of linking number Lk of supercoiled DNA. Given that a topoII is much smaller than the DNA it acts upon, how does a topoII discern the global DNA topology from the limited, local DNA conformational information it can access? To answer this question, we focus on DNA rather than protein conformations. Working with collaborators, we address the hypothesis that topological simplification by topoII is achieved by performing DNA segment passage and re-sealing only at hook-like DNA juxtapositions. To test this “hook juxtaposition hypothesis”, we use exact enumeration and Monte Carlo sampling of conformations with various preformed juxtaposition geometries. Results from cubic-lattice and worm-like chain models indicate that the hypothesis is likely valid because it consistently accounts for a wide range of experimental data.

Appointments, Cross Affiliations, Memberships

Editorial board member - Proteins: Structure, Function & Bioinformatics.

Courses Taught

BCH374Y1 Research Project in Biochemistry
BCH479H1 Advanced Seminar in Biochemistry
JBB2026H Protein Structure, Folding and Design
BCH472Y Advanced Summer Research Project in Biochemistry
BCH372Y Summer Research in Biochemistry
MMG1016H Gene and Protein Evolution

Awards

2019 — Fellow & National Lecturer, Biophysical Society of Canada
2017 — Siu Lien Ling Wong Visiting Fellow. The Chinese University of Hong Kong
2001-2010 — Canada Research Chair
2000 — Ontario Premier's Research Excellence Award