Pearl, Frances Mary Genevieve; (1998) Protein structural analysis: α-helices and their interactions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Helices are fundamental building blocks of many protein structures, and interactions between them play a crucial role in stabilising a protein's fold. This work updates and enhances the current knowledge of the nature of these interactions using the 3-dimensional coordinates of protein structures deposited in the Protein Data Bank. Having defined rigorous criteria for identifying regular a-helices, the geometric and physical properties of helix-helix interactions were studied. In contrast with previous studies, a systematic analysis of a large dataset of helix-helix interactions was undertaken. These interactions were divided into different geometric types, which were found to exhibit different physical properties. However, the range of interaction within each class was still very broad. Having studied the gross features of helix-helix interactions, an analysis of the residue packing at the interface was undertaken. Established manual methods were used to designate the packing classes of 36 highly interacting helix pairs from 11 proteins. These methods were found to be inappropriate for use with extensive amounts of data. Clearly an automatic method that allowed identification of previously undescribed packings would be desirable. Towards this end, contact maps and distance matrices were chosen as simple representations of helix-helix interactions amenable to automated computational analyses. Helix pairs with conserved packing interfaces within a set of globin structures were automatically clustered. However, those from a more general set of proteins failed to cluster. This led to a reassessment of the helix packing models. Although some helix interactions fit the idealised models, most are somewhat irregular. The helix packing we observe is driven solely by energetic considerations - to minimise free energy and generate an energetically stable globular protein. From this study it is clear that predicting a helix packing interaction in the absence of other contacts is unlikely to be successful.

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