(6js) Theories and Simulations for Liquid-Liquid Phase Separation in Biology

In molecular and structural biology, liquid-liquid phase separation underpins the formation of various newly discovered mesoscopic, liquid-like, functional assemblies/droplets in the cell not encapsulated by lipid membranes. These assemblies consist of multiple protein, DNA, and RNA molecules, termed “membraneless organelles” or “biomolecular condensates”. They compartmentalize intracellular environment into condensed and dilute phases, respectively, inside and outside of the droplet. The membraneless assemblies are critical in cellular signalling, homeostasis, gene regulation, and cell growth. Despite the recent flurry of experiments, their underlying biophysical mechanisms are rarely understood. I am particularly interested in the "sequence-specific" phenomena in biological phase separation. Biomolecules are heteropolymers with unique, precisely regulated sequences of amino acids or nucleic acids. Their phase separation has brought a new degree of freedom to polymer science: sequence specificity. To build a comprehensive understanding of the liquid-liquid phase separation in biology, new polymer physics has to be developed.

Review: Y.-H. Lin, J. D. Forman-Kay, and H. S. Chan (2018) Theories for sequence-dependent phase behaviors of biomolecular condensates, Biochemistry, 57, 2499

Research Experience:

I have been a joint postdoc of a theoretical group and an experimental group, closely collaborating with experimental biochemists and computational biologists. I am focusing on theoretical polymer physics and have been developing sequence-specific theories and computer simulation tools for the phase separation of charged intrinsically disordered proteins. In addition, in my PhD, I have studied the theoretical biophysics in the sequence-dependent structural effects in protein-RNA interaction. My research has provided a general theoretical framework for investigating phase separation and molecular recognition mechanisms of biomolecules.

Postdoctoral Project: "Theories for sequence-dependent phase behaviors of biomolecular condensates", under supervision of Hue Sun Chan, Department of Biochemistry, University of Toronto, AND Julie D. Forman-Kay, Molecular Medicine, The Hospital for Sick Children

PhD Dissertation: "The interplay between single-stranded binding proteins on RNA secondary structure", under supervision of Ralf Bundschuh, Department of Physics, Ohio State University

Future Directions:

Based on my achievements on researching phase separation in biology, I will investigate this topic by the following four approaches:

1. Advanced sequence-specific polymer theories: Based on the success of my polymer theories for charged biopolymers, I will build theories for other interactions in proteins and RNA, such as hydrophobicity, pi-electron interactions, and hydrogen bonds. More molecular and environmental details, for example protein side chains, pH values, and salt concentration, will be addressed. The kinetic properties of the phase separation droplets will also be studied by dynamic models.

Accomplished works: [1] Y.-H. Lin, J. D. Forman-Kay, & H. S. Chan (2016) Sequence- specific polyampholyte phase separation in membraneless organelles, Phys. Rev. Lett. 117, 178101 [2] Y.-H. Lin, J. Song, J. D. Forman-Kay, & H. S. Chan (2017) Random- phase-approximation theory for sequence-dependent, biologically functional liquid-liquid phase separation of intrinsically disordered proteins, J. Mol. Liq. 228, 176 [3] Y.-H. Lin & H. S. Chan (2017) Phase separation and single-chain compactness of charged disordered proteins are strongly correlated, Biophys. J. 112, 2043 [4] Y.-H. Lin, J. P. Brady, J. D. Forman-Kay, & H. S. Chan (2017) Charge pattern matching as a “fuzzy” mode of molecular recognition for the functional phase separations of intrinsically disordered proteins. New J. Phys. 19, 115003

2. Assess analytical theories using computer simulation: Computer simulations can complement the conceptual formulations proposed by analytical theories. Based on my experience in coarse-grained simulations for charged polymers, I will conduct simulations with more molecular details to assess and improve the theoretical approach so as to better rationalize phase separation phenomena.

Accomplished works: [1] S. Das, A. Eisen, Y.-H. Lin, and H. S. Chan (2018) A lattice model of charge-pattern-dependent polyampholyte phase separation, J. Phys. Chem. B, 122, 5418 [2] S. Das, A. Amin, Y.-H. Lin, and H. S. Chan (2018) Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters (in preparation)

3. Collaboration with experimentalists: Experiments are essential for evaluation of theories. I will keep my current successful mode of closely collaborating with experimental groups to receive first-hand experimental results which will help me develop relevant theories; at the same time I will contribute theoretical concepts and predictions to help develop new experimental targets. In addition I will also directly develop and apply my theories to the numerous published experiments of biological phase separation.

Accomplished work: J. P. Brady, P. J. Farber, A. Sekhar, Y.-H. Lin et al. (2017) Structural and hydrodynamic properties of an intrinsically disordered region of a germ-cell specific protein upon phase separation, PNAS 114, E8194

4. Bioinformatics: High-throughput database search requires simple but concise quantities and parameters. I will apply analytical theories to the various existing DNA, RNA, and protein databases to propose statistical ideas for categorizing and predicting phase separation phenomena.

Teaching Interests:

As a theoretical physicist working on polymer theory in the Department of Biochemistry in a Faculty of Medicine, I have been well experienced in conveying knowledges to people from different scientific and engineering disciplines. My teaching goal will be to prevent students from being constrained by a specific, fixed thinking context, but rather to be able to adapt various perspectives. My students will be able to find multiple strategies for the same problem and pick up the best-fit solution for different requirements and constraints, which, I believe, is one of the most precious skills conferred by engineering training. I have mentored two talented undergraduate research students during my postdoc, and have been a teaching associate in Department of Physics during my PhD study. My teaching strategy will be to urge students to study by themselves: before the class or research project, I will first assign study materials, textbook chapters and/or research papers; students will have to read the materials and write a summary about what they have learned and what they have not fully understood. My lecture will then be based on their summaries and questions, addressing those most complicated topics. I am particularly competent to teach physics-related engineering classes, for example thermodynamics and fluid dynamics. I am also competent to teach biophysics and polymer/biopolymer sciences classes due to my research background. Meanwhile, as I am well-experienced in computational methods for polymer and biomolecule solutions, I can also teach numerical methods and programming techniques.