Single-Molecule Biophysics. We develop and use single-molecule fluorescence methods to address key issues in molecular and cell biology. Single-molecule methods provide unprecedented views of structural and dynamic complexity in proteins and other biological macromolecules, allowing us to directly test biological models and theories (see review). A recent research focus is on Intrinsically Disordered Proteins (IDPs). While many proteins have well-defined 3-dimensional structures, IDPs have stretches of flexible sequence. IDPs are prevalent in proteomes, and their physics can play key roles in many cellular functions. Our single-molecule studies have shed light on the tunable nature of IDP structural landscapes (see paper), with implications for function (see paper) and diseases such as Parkinson’s and Alzheimer’s diseases (see paper 1, see paper 2). Recently, we have begun to probe mesoscale droplets formed by IDPs with RNA and other partners. These droplets are formed by liquid-liquid phase separation, a process believed to be mechanistically key in the dynamics of membraneless cellular organelles such as the nucleolus.
Watch a lecture (TSRI Faculty Lecture Series) about our work on single-molecule biophysics of protein disorder:
Read a recent interview describing some of our lab's emerging research directions:
Recent News and Outreach
- Chris and Mahdi defend their Ph.D. theses-congratulations!!!
- Read News-Medical interview on some of our lab’s emerging research directions, including the effects of 2D-crowding on folding of a Parkinson’s disease-linked IDP.
- Just out in Angewandte Chemie: our paper reporting on the discovery that crowding in two dimensions (on a membrane) can force an intrinsically disordered protein (IDP) α-synuclein to adopt a hidden partially membrane-bound structure. The work reveals new layers of complexity and control of IDP structure, with implications for biological function. The paper was designated as a Hot Paper in the journal, highlighted in the Biophysical Society IDP subgroup Newsletter and the TSRI News and Views. Congratulations to Priya and Mahdi!
- Ashok Deniz is named the 2016 TSRI Outstanding Mentor!"This was entirely a team effort - congratulations and many thanks to an amazing group of current and past graduate student and postoctoral mentees!!" Highlighted in TSRI News and Views.
- Just out in ChemBioChem: our paper describing dual unnatural amino-acid incorporation for fluorescent dye labeling of the cancer related protein p97. Conventional labeling methods are a limitation for this large, multicysteine protein. The work permits single-molecule FRET studies of this cellular machine. Highlighted on the front cover of the journal issue. Congratulations to Chris, and collaborators Eli (UArizona), Pete, Minjin and ChanHyuk!
- Out in Angewandte Chemie: our paper describing mechanistic studies of the disorder-order reaction of a multifunctional, cancer-related protein. We disovered alternative multi-step pathways for the reaction, that could be differentially tuned by biologically important phosphorylation and partner binding. Highlighted in Faculty of 1000 and TSRI News & Views. Congratulations to Priya, and St. Jude collaborators Richard and Diana!
- See our paper in Nature Communications reporting development/application of a microfluidic temperature-jump method for studies of biochemical kinetics/dynamics. One application was to use oscillating temperature inputs to test the low-pass output behavior of a simple folding system. Highlighted in TSRI News & Views. Congratulations to Yann, Priya, and UCSD collaborators Alex Groisman, Mark and Mike!
- Allan starts as an Assistant Professor at Baylor College of Medicine. Congratulations to Allan!
- Ashok to give lectures in 2014 at Cornell University (Physics), Biophysical Society Thematic Meeting and IDP GRC (discussion leader), in 2015 at Washington University, St. Louis (Biochemistry), the American Physical Society meeting, the American Society for Biochemistry and Molecular Biology meeting, conferences in Telluride and Zurich, a keynote lecture at the Biophysical Society meeting IDP subgroup symposium, in 2016 at the Protein Folding Dynamics GRC, Modeling & Dynamics workshop (VA), IDP GRS (faculty mentor), American Chemical Society meeting, University of Colorado, and in 2017, at the Biophysical Society Meeting (Symposium), conference in Telluride, and Computation/NMR GRC
- Just out in Nature: our paper describing single-molecule studies that revealed strikingly complex patterns of modulation of allostery in a disordered protein, providing a novel biophysical mechanism for tunable cellular function. Congratulations to Allan and our collaborators Peter Wright and Josephine Ferreon. See the paper. Highlighted in Nature News and Views, Chemical and Engineering News, Cell (Leading Edge Select), Faculty of 1000, and TSRI News and Views.
- See our review article on protein folding studies at single-molecule resolution, published in Chemical Society Reviews.
- Ashok to give a keynote lecture at the 2013 Chemical Biophysics Symposium (University of Toronto), invited lectures at the “Physics and Biology of Strongly Fluctuating Proteins” Symposium (University of Maryland) and the Scripps Research Faculty Lecture Series, and a Physical Chemistry Seminar (University of Wisconsin, Madison).
- Our recent paper directly tests a hypothesis of counteraction between the effects of opposing chemical chaperones on the structural features of α-synuclein. The paper is slated to appear in a special issue of PNAS on the chemical physics of protein folding.
- A recent paper sheds novel insight into the intricate mechanism of protein amyloid formation.
- Undergraduate Asha continues her internship in the lab
- Ashok to give invited talks in 2012 at Gordon Research Conferences (Protein Folding Dynamics; Intrinsically Disordered Proteins; Atomic and Molecular Interactions), St. Jude Children’s Research Hospital (Symposium on Biomolecular Structure, Dynamics and Function), Protein Society Meeting, and Pittcon
- High-School teacher Lesli does a summer internship in the lab
- Our recent Nature Methods Paper was highlighted in TSRI Press Release, Nature Methods News and Views, Physics Today Highlight, Faculty of 1000 Must Read Paper, ACS Chemical Biology Spotlight, PSI Nature Structural Biology Knowledgebase
- Crystal presents to visiting high-school science teachers
- Allan wins post-doctoral IDP subgroup award at the 2011 Biophysical Society Meeting
- Allan, Crystal and Ashok speak at the 2011 Biophysical Society Meeting