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

Proteins associated with cell membranes play an important role in enabling the transport of water
soluble molecules and ions across the fatty membranes which surround the cell or it's organelles. Most of these proteins, being insoluble in water, are difficult to study and relatively few structures have been determined with certainty by X-ray 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. The apparently small change of substituting one amino acid of the many hundreds or thousands in a protein, using the technique of site-directed mutagenesis can often cause profound effects on the properties of 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.



Graeme Cox

Membrane Biochemistry Group, John Curtin School of Medical Research



q11 - PC



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

In collaboration with workers in the Membrane Biochemistry and Neurophysiology Groups in the JCSMR, a wide variety of molecules has been investigated during the last year. These include viral ion channels, amino acid transport systems in bacteria and nerve cell receptors in mammals. Experimental results have been provided by workers in the laboratories. In addition, modelling has been carried out for workers in Melbourne, and a collaboration established with Professor G.D. Clark-Walker in the Research School of Biological Sciences in the ANU on mutants of yeast affected in the energy-tranducing ATP-synthesizing protein complex.

Much of the modelling is to assist in the progress of the laboratory work and as such appears in various PhD Theses. An example of work is that carried out in collaboration with Professor A.J.Pittard and his colleagues in the Microbiology Department of the University of Melbourne who are studying how a certain protein (tyrR protein) in Escherichia coli interacts with DNA. By using the crystal structure of a known related protein (Cro repressor) as a basis for modelling the TyrR protein it was possible to examine the amino acids likely to react with the DNA (see Figure).

The intention is to continue the work to try and help ascertain how the structures of the proteins being investigated in the laboratory relate to their known functions.

Appendix A -


What computational techniques are used?

The commercial molecular modelling packages Insight and Homology from MSI/Biosym are being used for modelling and their program Discover for energy calculations. The simulation of the protein 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


J. S. Hwang, J. Yang, A. J. Pittard, Critical Base Pairs and Amino Acid Residues for Protein-DNA Interaction between the TyrR Protein and TyrP Operator of Escherichia coli, J. Bact., 179, 1997, 1051-1058.

L. P. Hatch, G. B. Cox, S. M. Howitt, Glutamate residues at positions 219 and 252 in the a-subunit of the Escherichia coli ATP synthase are notfunctionally equivalent, In press, Biochim.Biophys.Acta.


Figure 1

Hypothetical model of the DNA-binding region of the TyrR protein showing amino acids thought to interact with the DNA ( after Hwang et al.)

- Appendix A