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Computational Biophysics; Biomolecular simulations
Research in the Chong lab involves the development and application of molecular simulation approaches to model a variety of biophysical processes. A summary of some of our research directions is provided below.
Weighted ensemble approaches for sampling rare events
To enable the efficient simulation of rare events (e.g. protein folding and binding processes), we have been developing approaches based on “weighted ensemble” path sampling, which introduces no bias into the dynamics. Using our high-performance implementation of this approach (WESTPA), we and others have demonstrated that this approach can enhance the efficiency of generating pathways and rate constants for rare events by orders of magnitude
Simulation of protein binding pathways and kinetics
Obtaining atomically detailed views of protein binding (and unbinding) processes has been a grand challenge in the field of biomolecular simulation due to the long timescales required. To tackle this difficult problem, we have been using weighted ensemble algorithms to generate pathways and rate constants for various protein binding processes, including those that involve intrinsically disordered peptides that fold only upon binding their intended partner proteins.
Design of protein conformational switches
The process of designing protein conformational switches involves a significant amount of educated guesswork in the laboratory. To aid in the rational design of protein switches, we have been developing simulation approaches with various levels of coarse-graining to efficiently predict the dynamics of these protein switches. We have been focusing on a particular class of protein-based switches that are engineered using a "mutually exclusive folding" strategy in which two formerly independent protein domains are fused together in such a way that at any moment in time, only one or the other protein can be folded, but not both.
- Gordon Bell Special Prize for HPC-Based COVID-19 Research, 2020
- Silicon Therapeutics Open Science Fellow, 2020
- University of Pittsburgh Arts & Sciences Bellet Teaching Excellence Award, 2017
- National Science Foundation CAREER Award, 2009-2014
- Carnegie Science Emerging Female Scientist Award, 2012
- Hewlett-Packard Outstanding Junior Faculty Award, 2008
- Frank M. Goyan Graduate Research Award in Physical Chemistry at UCSF, 2002
- Burroughs Welcome Graduate Research Fellowship, 2001-2002
- National Science Foundation Graduate Research Fellowship, 1998-2001
“Lessons Learned from a Ligand-Unbinding Stress Test for Weighted Ensemble Simulations,” Bogetti, A. T.; Yang, D. T.; Piston, H. E.; LeBard, D. N.; Chong, L. T. ACS Omega 2025, 10 25, 27617-27624.
“SHINE: Deterministic Many-to-Many Clustering of Molecular Pathways,” Chen, L.; Leung, J. M. G.; Zsigmond, K.; Chong, L. T.; Miranda-Quintana, R. A. J Chem Inf Model. 2025, 65 10, 4775-4782.
“Unsupervised Learning of Progress Coordinates during Weighted Ensemble Simulations: Application to NTL9 Protein Folding,” Leung, J. M. G.; Frazee, N. C.; Brace, A.; Bogetti, A. T.; Ramanathan, A.; Chong, L. T. J. Chem. Theory Comput. 2025, 21 7, 3691-3699.
“Illuminating an invisible state of the HIV-1 capsid protein CTD dimer using 19F NMR and weighted ensemble simulations,” Yang, D.T.; Chong, L.T.; Gronenborn, A.M. 2025, 122 8, 2420371122.
“Gating residues govern ligand unbinding kinetics from the buried cavity in HIF-2α PAS-B,” Silvestrini, M.L.; Solazzo, R; Boral, S; Cocco, M.J.; Closson, J.D.; Masetti, M; Gardner, K.H.; Chong, L.T. Protein Sci. 2024, 33 11, 5198.
“WEDAP: A Python Package for Streamlined Plotting of Molecular Simulation Data.” Yang, D.T.; Chong, L.T. J Chem Inf Model. 2024, 64 15, 5749–5755.
“Revisiting Textbook Azide-Clock Reactions: A "Propeller-Crawling" Mechanism Explains Differences in Rates,” Bogetti, A.T.; Zwier, M.C.; Chong, L.T. J Am Chem Soc. 2024. 146 18, 12828–12835.
“Effects of altered backbone composition on the folding kinetics and mechanism of an ultrafast-folding protein,” J. R. Santhouse, J. M. G. Leung, L. T. Chong*, W. S. Horne* Chem. Sci. 2024, 15, 675-682
“Direct observation of negative cooperativity in a detoxification enzyme at the atomic level by Electron Paramagnetic Resonance spectroscopy and simulation,” Xiaowei Bogetti, Anthony Bogetti, Joshua Casto, Gordon Rule, Lillian Chong, Sunil Saxena Protein Science 2023, 32 10, e4770
“LPATH: A semi-automated Python tool for clustering molecular pathways,” Anthony T Bogetti, Jeremy MG Leung, Lillian T Chong bioRxiv 2023, 8 17, 553774
“Structure-Based Experimental Datasets for Benchmarking of Protein Simulation Force Fields,” Chapin E Cavender, David A Case, Julian C-H Chen, Lillian T Chong, Daniel A Keedy, Kresten Lindorff-Larsen, David L Mobley, OH Ollila, Chris Oostenbrink, Paul Robustelli, Vincent A Voelz, Michael E Wall, David C Wych, Michael K Gilson arXiv 2023, 2303, 11056
“How does a ligand exit from a buried receptor cavity? Atomistic simulations of unbinding pathways with rigorous kinetics,” Marion L Silvestrini, Riccardo Solazzo, Matteo Masetti, Kevin H Gardner, Lillian T Chong Biophysical Journal 2023, 122 3, 20a
“Alternate conformational states of the HIV-1 capsid protein: Atomistic structures and dynamics of interconversion,” Darian T Yang, Angela M Gronenborn, Lillian T Chong Biophysical Journal 2023, 122 3, 308a
“Identification of Small Molecule Ligand Binding Sites On and In the ARNT PAS-B Domain,” Xingjian Xu, Leandro Pimentel Marcelino, Denize C Favaro, Marion L Silvestrini, Riccardo Solazzo, Lillian T Chong, Kevin H Gardner bioRxiv 2023, 11 3, 565595
“# COVIDisAirborne: AI-enabled multiscale computational microscopy of delta SARS-CoV-2 in a respiratory aerosol,” Abigail Dommer, Lorenzo Casalino, Fiona Kearns, Mia Rosenfeld, Nicholas Wauer, Surl-Hee Ahn, John Russo, Sofia Oliveira, Clare Morris, Anthony Bogetti, Anda Trifan, Alexander Brace, Terra Sztain, Austin Clyde, Heng Ma, Chakra Chennubhotla, Hyungro Lee, Matteo Turilli, Syma Khalid, Teresa Tamayo-Mendoza, Matthew Welborn, Anders Christensen, Daniel GA Smith, Zhuoran Qiao, Sai K Sirumalla, Michael O’Connor, Frederick Manby, Anima Anandkumar, David Hardy, James Phillips, Abraham Stern, Josh Romero, David Clark, Mitchell Dorrell, Tom Maiden, Lei Huang, John McCalpin, Christopher Woods, Alan Gray, Matt Williams, Bryan Barker, Harinda Rajapaksha, Richard Pitts, Tom Gibbs, John Stone, Daniel M Zuckerman, Adrian J Mulholland, Thomas Miller III, Shantenu Jha, Arvind Ramanathan, Lillian Chong, Rommie E Amaro The international journal of high performance computing applications 2023, 37 1, 28 - 44
“A Suite of Advanced Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v0.1],” Anthony T. Bogetti, Jeremy M.G. Leung, John D. Russo, She Zhang, Jeff P. Thompson, Ali S. Saglam, Dhiamn Ray, Rhea C. Abraham, James R. Faeder, Loan Andricioaei, Joshua L. Adelman, Matthew C. Zwier, David N. LeBard, Daniel M. Zuckerman, Lillian T. Chong bioRxiv 2022, 10 4, 510803
“Development and Validation of Fluorinated, Aromatic Amino Acid Parameters for Use with the AMBER ff15ipq Protein Force Field,” DT Yang, AM Gronenborn, and LT Chong J. Phys. Chem. A 2022, 126 14, 2286 - 2297
“Mechanistic Insights into Passive Membrane Permeability of Drug-Like Molecules from a Weighted Ensemble of Trajectories,” S Zhang, JP Thompson, J Xia, AT Bogetti, F York, AG Skillman, LT Chong, DN LeBard J. Chem. Inf. Model. 2022, 62 8, 1891 - 1904
“WESTPA 2.0: High-Performance Upgrades for Weighted Ensemble Simulations and Analysis of Longer-Timescale Applications,” JD Russo*, S Zhang*, JMG Leung*, AT Bogetti*, JP Thompson, AJ DeGrave, PA Torrillo, AJ Pratt, KF Wong, J Xia, J Copperman, JL Adelman, MC Zwier, DN LeBard, DM Zuckerman, LT Chong J. Chem. Theory Comput. 2022, 18 2, 638 - 649
“A glycan gate controls opening of the SARS-CoV-2 spike protein,” T Sztain, S Ahn, AT Bogetti, L Casalino, JA Goldsmith, E Seitz, RS McCool, FL Kearns, F Acosta-Reyes, S Maji, G Mashayekhi, JA McCammon, A Ourmazd, J Frankm, JS McLellan, LT Chong*, and RE Amaro Nat. Chem 2021, 13, 963 - 968
“A minimal, adaptive binning scheme for weighted ensemble simulations,” PA Torrillo*, AT Bogetti*, and LT Chong J. Phys. Chem. A 2021, 125 7, 1642 - 1649
“The RED scheme: Rate-constant estimation from pre-steady state weighted ensemble simulations,” AJ DeGrave*, AT Bogetti*, and LT Chong bioRxiv 2021, 154 11, 114111
“The Next Frontier for Designing Switchable Proteins: Rational Enhancement of Kinetics,” AT Bogetti, MF Presti, SN Loh, and LT Chong J. Phys. Chem. B 2021, 125 32, 9069 - 9077
“A twist in the road less traveled: The AMBER ff15ipq-m force field for protein mimetics,” AT Bogetti, HE Piston, JMG Leung, CC Cabalteja, DT Yang, AJ DeGrave, KT Debiec, DS Cerutti, DA Case, WS Horne, and LT Chong J. Chem. Phys. 2020, 153 6, 064101
“A suite of tutorials for the WESTPA rare-events sampling software,” AT Bogetti, B Mostofian, A Dickson, AJ Pratt, AS Saglam, PO Harrison, JL Adelman, M Dudek, PA Torrillo, AJ DeGrave, U Adhikari, MC Zwier, DM Zuckerman, and LT Chong, LiveCoMS 2019, 1 2, 10607
“Protein-protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent simulations,” AS Saglam and LT Chong Chem. Sci. 2019, 10, 2360-2372
“Large enhancement of response times of a protein conformational switch by computational design,” AJ DeGrave, JH Ha, SN Loh, and LT Chong, Nat. Commun. 2018, 9, 1013
“Links Between the Charge Model and Bonded Parameter Force Constants in Biomolecular Force Fields,” Ceruitt DS, Deibiec KT, Case DA, and Chong LT J. Chem. Phys. 2017, 147, 161730