people
|Faculty
|Lillian Chong
 |
Lillian Chong Department of Chemistry |
The central goal of the Chong lab is to use theory and simulation to understand how proteins fold, bind their partners, and catalyze reactions, with an emphasis on how malfunctions at the molecular level can be linked to clinical data for various diseases. To achieve this goal, we develop accurate approaches for simulation and subsequent analysis of protein structure and function.
Why simulate? Given the difficulty of using experiments to obtain structural details of the conformational changes of proteins upon folding or binding their partners, a natural alternative is to use atomistic molecular dynamics simulations, which provide the time resolution and detail necessary for monitoring the step-by-step progression of conformational changes. Due to the large computational cost required for simulating these conformational changes, we apply methods that take advantage of distributed computing by making effective use of a large ensemble of short, independent simulations.
Unstructured proteins. Recently, many proteins that perform essential roles in cellular signaling and regulatory pathways have been found to be unstructured, thus challenging the assumption that proteins must fold into well-defined, globular structures in order to carry out their functions. These proteins fold, or become ordered, only upon binding their partner proteins, suggesting a new paradigm of protein-protein recognition. Understanding this new paradigm is not only fundamental to biology, but could aid the development of therapeutics to prevent the malfunction of unstructured proteins due to mutations associated with diseases such as cancer. Questions to be addressed include:
1) What does “unstructured” really mean (e.g. are there any undetected structured regions)?
2) How do unstructured proteins recognize their targets?
3) How do these recognition events behave in vivo?
Tumor suppressor p53. Tumor suppressor p53 is a multidomain transcription factor that activates mechanisms for repair of DNA damage or elimination of damaged cells via programmed cell death. With more than 50% of human cancers linked to mutations in the p53 tumor suppressor gene, it is a protein of great biomedical interest. Studies related to p53 will involve analysis of its unstructured domains and their partner recognition events. These studies will not only add to our knowledge of how unstructured proteins recognize their targets, but build on our understanding of how p53 functions within the larger context of biological pathways in the cell.
Awards
UCSF Frank M. Goyan Graduate Research Award in Physical Chemistry, 2002; Burroughs Wellcome Graduate Research Fellowship, 2001-2002; NSF Graduate Research Fellowship, 1998-2001.
Selected Publications
"Kinetic computational alanine scanning: application to p53 oligomerization," L.T. Chong, W.C. Swope, J.W. Pitera, and V.S. Pande, J. Mol. Biol., 2006, 357, 1039-1049
"Dimerization of the p53 oligomerization domain: identification of a folding nucleus by molecular dynamics simulations," L.T. Chong, C.D. Snow, Y.M. Rhee, and V.S. Pande, J. Mol. Biol., 2005, 345, 869-878
"Direct hydroxide attack is a plausible mechanism for amidase antibody 43C9," L.T. Chong, P. Bandyopadhyay, T.S. Scanlan, I.D. Kuntz, and P.A. Kollman, J. Comp. Chem., 2003, 4, 1371-1377
"An alternative explanation for the catalytic proficiency of orotidine 5'-phosphate decarboxylase," T.S. Lee*, L.T. Chong*, J.D. Chodera, and P.A. Kollman (* equal authorship), J. Am. Chem. Soc., 2001, 123, 12837-12848
"Molecular dynamics simulation and free energy calculations applied to affinity maturation in antibody 48G7," L.T. Chong, Y. Duan, L. Wang, I. Massova, and P.A. Kollman, Proc. Natl. Acad. Sci USA, 1999, 96, 14330-14335
"Computation of electrostatic complements to proteins: a case of charge stabilized binding," L.T. Chong, S.E. Dempster, Z.S. Hendsch, L-P Lee, and B. Tidor, Protein Sci., 1998, 7, 206-210