Molecular modelling in structural biology.

Molecular modelling is a powerful methodology for analysing the three dimensional structure of biological macromolecules. There are many ways in which molecular modelling methods have been used to address problems in structural biology. It is not widely appreciated that modelling methods are often an integral component of structure determination by NMR spectroscopy and X-ray crystallography. In this review we consider some of the numerous ways in which modelling can be used to interpret and rationalise experimental data and in constructing hypotheses that can be tested by experiment. Genome sequencing projects are producing a vast wealth of data describing the protein coding regions of the genome under study. However, only a minority of the protein sequences thus identified will have a clear sequence homology to a known protein. In such cases valuable three-dimensional models of the protein coding sequence can be constructed by homology modelling methods. Threading methods, which used specialised schemes to relate protein sequences to a library of known structures, have been shown to be able to identify the likely protein fold even in cases where there is no clear sequence homology. The number of protein sequences that cannot be assigned to a structural class by homology or threading methods, simply because they belong to a previously unidentified protein folding class, will decrease in the future as collaborative efforts in systematic structure determination begin to develop. For this reason, modelling methods are likely to become increasingly useful in the near future. The role of the blind prediction contests, such as the Critical Assessment of techniques for protein Structure Prediction (CASP), will be briefly discussed. Methods for modelling protein-ligand and protein-protein complexes are also described and examples of their applications given.