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Membrane Protein and Lipid Structure and Dynamics
Membrane proteins have vital and diverse roles in cell signalling, transport, energy transduction, membrane fusion and other critical functions to the cell, and despite their clear importance to biology, they remain under-represented in structural databases, owing in part to difficulties in their crystallization and purification. They represent a fascinating challenge to biophysics, as the forces that govern the packing and dynamics of these proteins are inherently different from those of soluble proteins, and both solution and solid-state NMR have proven to be very useful tools in probing the structure and biophysics of membrane proteins.
One area of interest is the fusion systems of viruses. Enveloped viruses, such as the HIV and the influenza virus, are coated with a phospholipid membrane, and highly-conserved fusion proteins in this membrane are responsible for performing the merger of the viral and host-cell membranes on infection. Accordingly, fusion proteins are an important pharmaceutical target, but details of their mechanism remain poorly understood: how does a protein stabilize the high-energy intermediates in curving two membranes toward each other and finally in puncturing a hole between them? Research in our group focuses on the structure, dynamics and lipid perturbations of fusion proteins, sub-components of fusion proteins and other membrane pore systems. We use biochemical methods to produce isotopically-enriched membrane proteins of the measles, SARS, HIV and influenza viruses, then study the structure and membrane interaction of these proteins by solution and solid-state NMR.
High-Resolution Structure and Dynamics by NMR
Solution- and solid-state NMR are powerful tools for probing the structure and dynamics of biomolecules. The solid-state anisotropic Hamiltonian contains rich, orientation-dependent information on molecular structure and dynamics, and it can be readily measured in insoluble proteins as well as soluble proteins and nucleic acids. The isotropic Hamiltonian of solution NMR, by contrast, can be used to probe thousands of sites in a single experiment with a wide range of applications for soluble biomolecules. The two methods are highly complementary, and over the last 30 years, significant progress has been made in generating high-resolution structures and dynamic maps of molecules using NMR.
Our research aims to develop new theoretical, experimental and computational tools to further enhance the quality of structural and dynamic information produced by solution and solid-state NMR. Our first area of interest is in improving the quality of distance restraints to improve the precision and accuracy of molecular structures by NMR. This project focuses on developing new computational tools to model protein structures using NMR data. Our second area of interest is in developing new methods for studying and mapping molecular dynamics at high resolution, in order to isolate the rates and motional modes of functional groups in biomolecules. This project uses solid-state NMR of protein micro-crystals to map out the dynamics of proteins and enzymes and correlate these to function.
- Lorieau JL, Louis JM, Bax A (2011) Whole-Body Rocking Motion of a Fusion Peptide in Lipid Bilayers from Size-Dispersed 15N NMR Relaxation. J Am Chem Soc 133:14184-14187.
- Lorieau JL, Louis JM, Bax A (2011) Helical Hairpin Structure of Influenza Hemagglutinin Fusion Peptide Stabilized by Charge−Dipole Interactions between the N-Terminal Amino Group and the Second Helix. J Am Chem Soc 133: 2824-2827.
- Lorieau JL, Louis JM, Bax A (2010) The complete inﬂuenza hemagglutinin fusion domain adopts a tight helical hairpin arrangement at the lipid:water interface. Proc Nat’l Acad Sci USA 107:11341-11346.
- Lorieau JL, Yao L, Bax A (2008) Liquid crystalline phase of G-tetrad DNA for NMR study of detergent-solubilized proteins. J Am Chem Soc 130:7536-7537.
- Lorieau JL, Day LA, McDermott AE (2008) Experimental Molecular Dynamics of an Intact Virus : Solid-State NMR Site-Speciﬁc Order Parameters of the Pf1 bacteriophage. Proc Nat’l Acad Sci USA 105:10366-10371.
- Lorieau JL, McDermott AE (2006) Conformational Flexibility of a Microcrystalline Globular Protein : Order Parameters by Solid-State NMR. J Am Chem Soc 128:11505-11512.
BSc (Hon. Chem., First Class Honours), University of Alberta, 2001
PhD, Columbia University, 2006
Research Fellow at The National Institutes of Health, 2007-2012