Department of Biophysics and Biophysical Chemistry
School of Medicine
B.S. 1993, University of Michigan
Ph.D. 1999, Harvard University
725 N. Wolfe Street
Baltimore, MD 21205
Our lab uses a combination of computational and experimental approaches to try to understand the molecular details governing the function of protein complexes involved in intercellular communication. The complexes that are studied include ionotropic glutamate receptors (iGluRs). iGluRs are ligand-gated ion channels that mediate the majority of excitatory synaptic transmission in the brain. They are important in synaptic plasticity, memory, and cognition, and they are associated with conditions that include autism, epilepsy, Parkinson's disease, and schizophrenia. The binding of neurotransmitter molecules to the ligand-binding domains of iGluRs drives the opening of the receptor's transmembrane pore, allowing cations to flow into the cell, which in turn triggers a nerve impulse.
Computationally, we apply methods in molecular simulation and statistical thermodynamics to estimate the free energies, kinetics, and pathways associated with ligand binding and protein conformational transitions, with the goal of generating experimentally testable predictions. Macromolecular modeling is also applied towards computational protein design. Experimentally, we pursue structural (X-ray crystallography, small-angle X-ray scattering, etc.) and biochemical studies to help understand macromolecular structure-function relationships.
Yao, Y., Belcher, J. Berger, A.J., Mayer, M.L., and Lau, A.Y. (2013) Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics. Structure 21: 1788-1799.
Lau, A.Y., Salazar, H., Blachowicz, L., Ghisi, V., Plested, A.J.R., and Roux, B. (2013) A conformational intermediate in glutamate receptor activation. Neuron 79: 492-503.
Lau, A.Y., and B. Roux. (2011) The hidden energetics of ligand-binding and activation in a glutamate receptor. Nat. Struct. Mol. Biol. 18:283-287.
Numano, R., Szobota, S., Lau, A.Y., Gorostiza, P., Volgraf, M., Roux, B., Trauner, D., and Isacoff, E.Y., (2009) Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR. Proc Natl Acad Sci. 106: 6814-6819.
Lau, A.Y., and B. Roux. (2007) The free energy landscapes governing conformational changes in a glutamate receptor ligand-binding domain. Structure 15:1203-1214.
Lau, A.Y., and D.I. Chasman. (2004) Functional classification of proteins and protein variants. Proc. Natl. Acad. Sci. USA 101:6576-6581.
Ramachandran, N., Hainsworth, E., Bhullar, B., Einstein, S., Rosen, B., Lau, A.Y., Walter, J.C. and LaBaer, J. (2004)Self-assembling protein microarrays. Science. 305:86-90.
Lau A.Y., M.D. Wyatt, B.J. Glassner, L.D. Samson, and T.E. Ellenberger. (2000) Molecular basis for discriminating between normal and damaged bases by the human alkyladenine glycoslase, AAG. Proc. Natl. Acad. Sci. USA 97:13573-13578.
Lau A.Y., O.D. Schärer, L. Samson, G.L. Verdine, and T. Ellenberger. (1998) Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide-flipping and base excision. Cell 95:249-258.