Munro, Robin Edward James; (1999) Protein structure prediction and modelling. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The prediction of protein structures from their amino acid sequence alone is a very challenging problem. Using the variety of methods available, it is often possible to achieve good models or at least to gain some more information, to aid scientists in their research. This thesis uses many of the widely available methods for the prediction and modelling of protein structures and proposes some new ideas for aiding the process. A new method for measuring the buriedness (or exposure) of residues is discussed which may lead to a potential way of assessing proteins' individual amino acid placement and whether they have a standard profile. This may become useful in assessing predicted models. Threading analysis and modelling of structures for the Critical Assessment of Techniques for Protein Structure Prediction (CASP2) highlights inaccuracies in the current state of protein prediction, particularly with the alignment predictions of sequence on structure. An in depth analysis of the placement of gaps within a multiple sequence threading method is discussed, with ideas for the improvement of threading predictions by the construction of an improved gap penalty. A threading based homology model was constructed with an RMSD of 6.2A, showing how combinations of methods can give usable results. Using a distance geometry method, DRAGON, the ab initio prediction of a protein (NK Lysin) for the CASP2 assessment was achieved with an accuracy of 4.6Å. This highlighted several ideas in disulphide prediction and a novel method for predicting which cysteine residues might form disulphide bonds in proteins. Using a combination of all the methods, with some like threading and homology modelling proving inadequate, an ab initio model of the N-terminal domain of a GPCR was built based on secondary structure and predictions of disulphide bonds. Use of multiple sequences in comparing sequences to structures in threading should give enough information to enable the improvements required before threading can be-come a major way of building homology models. Furthermore, with the ability to predict disulphide bonds: restraints can be placed when building models, ab initio or otherwise.

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