Norman Hascoe Distinguished Lecture Series

Nanoscience at the Physics-Biology Interface: Studies on Biomembrane Proteins

Anthony Watts
Bionanotechnology IRC
University of Oxford, Oxford, UK

Understanding how nanoscale interactions define biological function has been one of our goals in the study of the proteins of cell membranes. Distance constraints in the nm – pm range and dynamics in the ps –ns range have been measured in fully functional membrane proteins using novel applications of solid state NMR, in which the sensitivity of second order perturbations (dipolar and quadrupolar) of the spin Hamiltonian are exploited. Force measurements at the nN - pN scale involved in protein stability and folding are also being explored using liquid AFM studies of membrane peptides. Computational methods supplement this work, and have been extended to focus on how the sub-nm pore size of ion channels determine their selectivity and switching.

These biophysical methods have been applied to investigate specific drugs (peptic ulcer, ischemia, HIV-1 and schizophrenia therapies) at their binding sites, and to give indications about how small (Mr~ 200 – 500) molecules can control the function of very large (Mr ~ 100 – 280k) membrane-embedded target proteins (ATPases, ligand gated ion channels and photoreceptors) [1-6]. In particular, new insights into the major contribution of electronic contributions and local Brownian-driven dynamics to activation and inhibition, through cation and orbital sharing, have been identified [7-12]. 17O, as a new NMR nucleus in biology [13-16], in addition to the more usual 13C, 15N, 2H and 19F, is being used to define H-bonding and bond lengths to <1pm. The AFM studies on membrane proteins shows how specific amino acids have an anchoring effect and contribute to the tethering of peptides and proteins in membranes, and MD simulations reveal the magnitude and discrete steps involved in unfolding process.

[1]. Watts, A. (2004), Nature Drug Discovery, (in press);

[2]. Watts, A. (1999). Curr. Op. in Biotech, 10, 48-53;

[3]. Watts, A. (1999). Pharmacy & Pharmacology Communications, 5, 7-13;

[4]. Ulrich,A.S., Wallat, I., Heyn, M.P. & Watts, A. (1995) Nature Structural Biology, 2, 190-192;

[5]. Gröbner, G., Burnett, I.J., Glaubitz, C., Choi, G., Mason, A.J. & Watts, A. (2000) Nature, 405, 810-813;

[6]. Glaubitz, C., Burnett, I., Gröbner, G., Mason, J. & Watts, A. (1999) J. Am. Chem. Soc. 121, 5787-5794;

[7]. Williamson, P.T.F., Watts, J.A., Addona, G.H. Miller, K.W. and Watts, A. (2001) PNAS, 98, 2346-2351;

[8]. Grage, S.L., Watts, J.A., and Watts, A. (2004) J. Mag. Res., 166, 1-10;

[9]. Middleton, D.A., Robins, R., Feng, X., Levitt, M.H., Spiers, I.D., Schwalbe, C., Reid, D.G. & Watts, A. (1997) FEBS Letts. 410, 269-274;

[10]. Middleton, D.A., Rankin, S., Esmann, M. and Watts, A. (2000) PNAS, 97, 13602-13607;

[11]. Williamson, P.T.F., et al., (1998) Biochemistry, 37, 10854-10859;

[12]. Williamson, P.T.F., Watts, J.A., Addona, G.H. Miller, K.W. and Watts, A. (2001) PNAS, 98, 2346-2351;

[13]. Pike, K.J., Lemaitre, V., Kukol, A., Anupöld, T., Samoson, A., Howes, A.P., Watts, A., Smith, M.E. and Dupree, R. (2004) J. Phys. Chem. B, 108, 9256-9263;

[14]. Lemaitre, V., Pike, K.J., Watts, A., Anupold, T., Samoson, A., Smith, M.E. and Dupree, R. (2003) Chemical Physics Letters, 371, 91 – 97;

[15]. Lemaitre, V., Pike, K.J., Smith, M.E., Dupree, R. and Watts, A. (2004) J.A.C S. (in press);

[16]. Lemaitre, V., Smith, M.E. and Watts, A. (2004) Solid state NMR, (in press). See also (

Monday, October 4, 2004
4:00 PM

(Refreshments will follow, with a panel discussion at 5:30 PM.)

© 2004 Department of Physics, University of Connecticut
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