Lucy R. Forrest, Ph.D.
Computational Structural Biology Section
Building 35, Room 3D991
35 Convent Drive
Bethesda, MD 20892-3761
Membrane-embedded proteins are essential components of cellular organisms, allowing cells to communicate with their surroundings by providing bridges through the barrier that the lipid membrane forms. Our group is interested in understanding the mechanisms of membrane proteins using computational and theoretical approaches. Of particular interest are transporter proteins, which capture the chemical potential energy of ionic gradients (across the membrane) to facilitate movement of essential chemicals, or unwelcome toxic compounds, into and out of the cell. A fundamental question is how transporters achieve the required levels of specificity for a given chemical, or substrate, and how the protein-substrate interaction is coupled to transport of ions such as sodium. A further puzzle is how the transporter undergoes the requisite changes in shape to allow access of the substrate binding sites to either side of the membrane, while also preventing leakage (see Figure).
An essential characteristic of our work is that the hypotheses and interpretations we provide be connected with experimental evidence. Close and long-standing collaborators include the Rudnick group at Yale University, with whom we have studied transport of neurotransmitters such as serotonin. We also study glutamate transport in collaboration with the Kanner group, and acetylcholine transport with the Schuldiner lab, both from Hebrew University, Jerusalem. An ongoing collaboration with the Ziegler group at MPI Frankfurt/University of Regensburg combines computational, structural and biochemical studies on an osmolyte transporter. An aspect we find particularly fascinating is the role of repeated elements in the mechanisms of transport conformational change, which provide an elegant pseudo-symmetry and degeneracy to the system so that a single protein can adopt two pseudo-symmetric states (see Figure).
We apply a range of computational tools to understand these processes at atomic detail. To date, those techniques include sequence analysis and continuum electrostatics, as well as protein structure prediction and molecular dynamics simulation, tools for which we also develop ourselves.
Adhikary S, Deredge DJ, Nagarajan A, Forrest LR, Wintrode PL, Singh SK. Conformational dynamics of a neurotransmitter:sodium symporter in a lipid bilayer. Proc Natl Acad Sci U S A. 2017;114(10):E1786-E1795.
Mulligan C, Fenollar-Ferrer C, Fitzgerald GA, Vergara-Jaque A, Kaufmann D, Li Y, Forrest LR, Mindell JA. The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism. Nat Struct Mol Biol. 2016;23(3):256-63.
Yaffe D, Vergara-Jaque A, Forrest LR, Schuldiner S. Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis. Proc Natl Acad Sci U S A. 2016;113(47):E7390-E7398.
Forrest LR. Structural Symmetry in Membrane Proteins. Annu Rev Biophys. 2015;44:311-37.
Fenollar-Ferrer C, Patti M, Knöpfel T, Werner A, Forster IC, Forrest LR. Structural fold and binding sites of the human Na⁺-phosphate cotransporter NaPi-II. Biophys J. 2014;106(6):1268-79.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
Biomedical Engineering and Biophysics
This page was last updated on September 11th, 2018