Dr. Lau's lab uses a combination of computational and experimental approaches to try to understand the atomic and 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 central nervous system. iGluRs are important in synaptic plasticity, which underlies learning and memory. Receptor dysfunction has been implicated in a number of neurological disorders. The binding of neurotransmitter molecules to the ligand-binding domains of iGluRs drives the opening of the associated transmembrane pore, allowing cations to flow into the cell, which in turn triggers a nerve impulse.
Computationally, Dr. Lau and his team apply methods in molecular simulation and statistical thermodynamics to estimate the free energies and kinetics associated with ligand binding and protein conformational transitions. Their goal is to generate testable predictions that can help guide experimental investigations as well as help interpret experimental observations. Computational protein design is also explored. Experimentally, they pursue structural studies primarily using x-ray crystallography to help characterize macromolecular structure-function relationships. Biophysical insights can collectively be applied to the design of therapeutic agents.
Yao Y, Belcher J, Berger AJ, Mayer ML, Lau AY. "Conformational analysis of NMDA receptor GluN1, GluN2, and GluN3 ligand-binding domains reveals subtype-specific characteristics." Structure. 2013 Oct 8;21(10):1788-99. doi: 10.1016/j.str.2013.07.011. Epub 2013 Aug 22.
Lau AY, Salazar H, Blachowicz L, Ghisi V, Plested AJ, Roux B. "A conformational intermediate in glutamate receptor activation." Neuron. 2013 Aug 7;79(3):492-503. doi: 10.1016/j.neuron.2013.06.003.
Lau AY, Roux B. "The hidden energetics of ligand binding and activation in a glutamate receptor." Nat Struct Mol Biol. 2011 Mar;18(3):283-7. doi: 10.1038/nsmb.2010. Epub 2011 Feb 13.
Contreras JE, Chen J, Lau AY, Jogini V, Roux B, Holmgren M. "Voltage profile along the permeation pathway of an open channel." Biophys J. 2010 Nov 3;99(9):2863-9. doi: 10.1016/j.bpj.2010.08.053.
Kollewe A, Lau AY, Sullivan A, Roux B, Goldstein SA. "A structural model for K2P potassium channels based on 23 pairs of interacting sites and continuum electrostatics." J Gen Physiol. 2009 Jul;134(1):53-68. doi: 10.1085/jgp.200910235.