A Combined Molecular Biological and Computer Graphics Study of Biologically Active Proteins

Principal Investigator

Frank Gibson

Membrane Biochemistry Group

John Curtin School of Medical Research

A major function of proteins associated with cell membranes is to enable the transport of water soluble molecules and ions across the fatty membranes which surround the cell or its organelles. Because these proteins are themselves often insoluble in water they are difficult to study and relatively few structures have been determined with certainty by crystallography or NMR. Molecular modelling provides one method of attempting to visualize their structures and can provide a valuable adjunct to concurrent studies in the laboratory. Substitution of one amino acid in the structure by another, using site-directed mutagenesis can often cause profound effects on the cell. Modelling of the normal and mutant structures allows predictions to be made about structure/function relationships. This approach is particularly useful in the case of transmembrane segments of protein channels which can be predicted to have a helical structure.

A wide variety of molecules has been investigated during the last year, including viral ion channels, amino acid transport systems and nerve cell receptors. Experimental results have been provided by workers in the Membrane Biochemistry and Neurophysiology Groups in JCSMR and modelling has been carried out for workers in the Universities of Melbourne and East Anglia, and in the Research School of Biological Sciences in the ANU.


Graeme B. Cox

Membrane Biochemistry Group

John Curtin School of Medical Research


q11 - VPP, PC

What are the results to date and the future of the work?

Modelling of the transmembrane helices of various ion-channels has continued. As an example, Figure 1 shows a hypothetical viral ion channel formed by the "NB" protein of the Influenza B virus which transports sodium ions. The model represents a view down a pentamer of transmembrane amino acid helices, the pore in the centre allowing the passage of the sodium ion as shown. If this model reflects the real situation it could be predicted that substitution of one or more of the small amino acids lining the pore by bulky amino acid(s) might inhibit the passage of sodium ions; such experiments are possible using current techniques.

Further modelling of proteins of the subunits of ATP synthase and of other ion channels has continued during the year as an extension of the on-going laboratory work on these proteins.

- Appendix A

Fig.1 A model pentamer of a transmembrane helix peptide from the Influenza B virus forming a sodium channel with a sodium ion in the channel.

What computational techniques are used?

The commercial molecular modelling packages Insight and Homology from MSI are being used for modelling and their program Discover for energy calculations. The simulation of the structures in which we are interested require extensive calculations for energy minimizations and molecular dynamics. The use of the supercomputer not only allows many more structures to be examined but frees our Iris for further modelling and computations on smaller molecules


S.C., Pillar, G.D., Ewart, A.,Premkumar, G.B.Cox and P.W. Gage, Vpr Protein of human immunodeficiency virus type 1 forms cation-selective channnels in planar lipid bilayers, Proc. Nat. Acad. Sc. USA, 93, 93, 111-115 (1996).