Nandi, Chitralekha Lilian; (1994) Analysis of sidechain interactions within and between proteins. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis deals with the analysis of protein structures and their complexes which has been made possible by the high number of good quality protein structures available. It essentially falls into parts whereby the first part deals with the role of sidechains within proteins and the second part deals with the role of sidechains between proteins. For the first part of this thesis a statistical analysis of the atomic environments around the sidechains of arginine and phenylalanine was performed. A database of 62 high resolution protein structures was used. The contact preferences and the geometrical distributions of 19 different atom types around the sidechains were studied. The results show that polarity, covalent constraints, volume occlusion and solvent accessibility are the key factors governing the packing arrangements of the atoms around the sidechains. Theoretical methods were used then to try and 'predict' these experimental atom-sidechain distributions. For this purpose a commercially available energetics package was used. In due course it is hoped that the results of these studies will be successfully incorporated into a novel algorithm regarding the development of new drug molecules. Preliminary results are promising. The second part of this thesis presents an extensive analysis of the mode of binding of peptidic inhibitors to the aspartyl proteinase endothiapepsin. Endothiapepsin is an enzymic protein which belongs to the same family as the medically important HIV-1 protease. A general pattern emerged whereby the inner residues of the peptidic inhibitors were found to bind more tightly to the enzyme than the outer residues. The results of this study together with information about the binding constants of the inhibitors in their complexes have led to the suggestion of alternative designs of the inhibitors which may function equally well or even better.

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