Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
South Parks Road
Oxford OX1 3QU

Tel: +44 (0)1865 613200
Fax: +44 (0)1865 613201
Image showing the global movement of lipids in a model planar membrane
Matthieu Chavent, Sansom lab
Anaphase bridges in fission yeast cells
Whitby lab
Lactose permease represented using bending cylinders in Bendix software
Caroline Dahl, Sansom lab
Epithelial cells in C. elegans showing a seam cell that failed to undergo cytokinesis
Serena Ding, Woollard lab
Collage of Drosophila third instar larva optic lobe
Lu Yang, Davis lab
First year Biochemistry students at a practical class
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Phil Biggin
Computational Approaches to Receptor Dynamics and Ligand-Binding

Co-workers: Maria Musgaard (Benzon Fellow), Ole Juul Andersen (Carlsberg Fellow), Irfan Alibay, Julia Busch, Lea Sefer, Marc Dämgen, Naushad Velgy, Joe Bluck, Zhiyi (William) Wu, Will Glass, Karan Bali and Amy Kidd.

Website: http://sbcb.bioch.ox.ac.uk/bigginlab

We are developing and applying computational methods to examine conformational changes and properties of ligand-binding that occur within receptor proteins. We are particularly interested in two distinct families of receptors: 1. The ionotropic glutamate receptors and 2. The nicotinic acetylcholine receptor. Although there has been a recent increase in the amount of structural information available, many questions still remain concerning the dynamics associated with these processes (see Figure 1). For example, how does the binding of agonist cause the transmembrane domain to open? What determines whether an agonist will act as a full or partial agonist? How can channel opening be modulated? How do certain compounds interfere with the process of desensitization? We use molecular dynamics to examine the molecular motion of these receptors at the atomic level (see Figures 2 and 3 for recent examples).

Furthermore, via free energy calculations, we are able to make quantitative predictions that can be tested experimentally. A better understanding of the manner in which ligand-gated ion channels work should be useful in the design of new drug treatments for a range of diseases including Alzheimer's, Parkinsons's, and epilepsy.

We are also interested in conformational change in a broader sense. Two areas that we are currently focussing on are 1. How molecular motion has evolved. 2. How best to describe transitions between discrete states. The conservation of structure (ie. fold) has been discussed for a long time. We are interested in trying to understand how well molecular motion is conserved amongst protein folds. Our results so far have demonstrated that large conformational changes are dictated by fold, but smaller higher-frequency motions are dictated by sequence.

Recent Selected Publications

  1. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S & Biggin PC. (2017) Predictions of Ligand Selectivity from Absolute Binding Free Energy Calculations.  JACS doi: 10.1021/jacs.6b11467
  2. Alcaino C, Musgaard M, Minguez T, Mazzaferro S, Faundez M, Iturriaga-Vasquez P, Biggin PC, Bermudez I. (2017) Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors. J Biol Chem. 292:551-562. 
  3. Heifetz A, James T, Morao I, Bodkin MJ, Biggin PC.  (2016)  Guiding lead optimization with GPCR structure modeling and molecular dynamics.  Curr Opin Pharmacol. 30:14-21.
  4. Musgaard M, Biggin PC.  (2016)  Steered Molecular Dynamics Simulations Predict Conformational Stability of Glutamate Receptors. J Chem Inf Model. 56:1787-97.
  5. Sridhar A, Johnston AJ, Varathan L, McLain SE, Biggin PC.  (2016) The solvation structure of alprazolam.  Phys Chem Chem Phys. 18:22416-25.
  6. Lee J, Sands ZA, Biggin PC. (2016)  A Numbering System for MFS Transporter Proteins.  Front Mol Biosci. 3:21
  7. Dawe GB, Musgaard M, Aurousseau MRP, Nayeem N, Green T, Biggin PC & Bowie D. (2016) Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes.  Neuron. 89:1264-76.
  8. Heifetz A, Storer RI, McMurray G, James T, Morao I, Aldeghi M, Bodkin MJ, Biggin PC.  (2016) Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.
    ACS Chem Biol. 11:1372-82.
  9. Aldeghi M, Heifetz A, Bodkin MJ, Knapp S, Biggin PC.  (2016) Accurate calculation of the absolute free energy of binding for drug molecules. Chem Sci. 2016 7:207-218.
  10. Braun N, Lynagh T, Yu R, Biggin PC, Pless SA.  (2016)  Role of an Absolutely Conserved Tryptophan Pair in the Extracellular Domain of Cys-Loop Receptors. ACS Chem Neurosci. 7:339-48.
More Publications...

Research Images


Figure 1: Schematic of iGluR function. Only two of the four subunits are shown for clarity. The channel exists in a resting state prior to ligand binding (A). Upon the binding of glutamate there is a conformational change that pulls the M2 helices apart and allows the passage of cations (B). After a period of time the channel undergoes the process of desensitization whereby there is a further conformational change and closes the channel (C). The precise mechanism of these changes is still unclear and is under current investigation in the laboratory


Figure 2: Work in our laboratory as shown that the presence of different ligands correlates with the degree of protein flexibility in the GluR2 ligand-binding domain (LBD). Reading from left to right, when glutamate is bound there is least flexibility in the LBD compared to when no ligands are bound (Open-Apo) where there is the greatest flexibility


Figure 3: NMDA receptors do not show a correlation between the different agonists bound and the degree of D1-D2 cleft opening (as seen for AMPA receptors). Therefore the way in which NMDA receptors distinguish different agonists must be different. The conformational properties of the hinge region in NMDA receptors may provide such a mechanism. The backbone hydrogen bonding in the strands that link D1 to D2 can adopt two alternative hydrogen-bonding interactions depending on the type of agonist present


Contact: philip.biggin@bioch.ox.ac.uk
Graduate Student and Postdoctoral Positions: Enquiries with CV welcome
Website: http://sbcb.bioch.ox.ac.uk/bigginlab