Aims

• To explain the steps involved in comparative protein modelling.
• To describe how 3D transformations are used in some modelling steps.
• To describe methods for protein fold recognition.

Objectives

After this lecture you will:

• know the steps involved in comparative protein modelling;
• understand how fragment-fitting and rotamers are used in the modelling process;
• understand how structures and structural fragments can be clustered;
• understand how to compose 3D transformations;
• understand how to use 3D transformations to model protein fragments;
• understand different approaches to protein fold recognition.

Supplementary Material

Rob Russell has written A Guide to Structure Prediction that includes practical advice and links to useful software.

Several of the figures shown in the lecture were taken from Professional gambling. This is an updated version of the article: R.Rodriguez, R. and Vriend, G. (1997) "Professional gambling", in Vergoten, G. and Theophanides, T. (eds.) Proceedings of the NATO Advanced Study Institute on Biomolecular Structure and Dynamics: Recent Experimental and Theoretical Advances.

Rob Russell has written A Guide to Structure Prediction that includes practical advice and links to useful software.

Protein structure prediction: a practical approach, edited by Michael J.E. Sternberg, contains a collection of articles covering several of the areas mentioned in this lecture.

Principles of Protein Structure, Comparative Protein Modelling and Visualisation has material from an internet course on protein structure and modelling.

ModBase is a database of three-dimensional protein models produced by comparative modelling.

A short discussion of state-of-the-art techniques in protein structure prediction, and their applications, is given in:

Baker, D., and Sali, A. (2001) Protein structure prediction and structural genomics. Science, 294, 93-96. (David Baker's publication list)

The use of a backbone-dependent rotamer library in modelling protein side-chains is described in:

Bower, M.J., Cohen, F.E. and Dunbrack, R.L. (1997) Prediction of Protein Side-chain Rotamers from a Backbone-dependent Rotamer Library: A New Homology Modeling Tool. J. Mol. Biol., 267, 1268-1282 (PubMed)

A constraint logic programming approach to side-chain placement is described in:

Swain, M.T. and Kemp, G.J.L. (2001) A CLP approach to the protein side-chain placement problem. In Walsh, T. (ed.) Principles and Practice of Constraint Programming - CP2001, Lecture Notes in Computer Science (vol. 2239), Springer-Verlag, Berlin, pp 479-493. (PDF)

For more information on fold recognition and threading, I recommend the following early articles:

Bowie, J.U., Lüthy, R. and Eisenberg, D. (1991) A Method to Identify Protein Sequences That Fold into a Known Three-Dimensional Structure. Science, 253, 164-170.

Jones, D.T., Taylor, W.R. and Thornton, J.M. (1992) A new approach to protein fold recognition. Nature, 358, 86-89.

Sippl, M.J. and Weitckus, S. (1992) Detection of Native-Like Models for Amino Acid Sequences of Unknown Three-Dimensional Structure in a Data Base of Known Protein Conformations. Proteins: Structure, Function and Genetics, 13, 258-271 (Manfred Sippl's publication list)

The pairwise pseudo-energy terms and solvation potentials used in GenTHREADER are described in:

Jones, D.T. (1999) GenTHREADER: an efficient and reliable protein fold recognition method for genomic sequences. J. Mol. Biol., 287, 797-815 (PubMed)