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A series of head to head linked dimers of heterocyclic amino acids has been prepared for investigation of affinity and selectivity in binding to the minor groove of DNA. The selection of targets for synthesis was led by computer based design. Several novel dicarboxylic acid linkers including indoles, phenanthrenes, a fluorenone, and a bisbenzothiophene have been included. Analysis of binding to DNA by footprinting showed high affinity for compounds derived from 2,7-dihydrophenanthrene dicarboxylic acid and a predominant selectivity for AT rich regions containing at least 4 AT pairs but with the ability to span up to two CG base pairs.

Lucifer is a suite of programs for the conformational study of drugs, proteins and other biomolecules. The overall architecture and operation of the suite is outlined with worked examples. New procedures are also described for the identification of secondary structure template similarity based on theorem-proof algebra and for the rapid evaluation of the hydrophobic packing of a protein conformation. These are discussed in relation to the molecular-graphics modelling of chloramphenicol acetyltransferase. Although Lucifer is of proven worth for the study of biological peptides and for protein modelling against homologues, its applicability to de novo protein structure prediction is untested. A preliminary study of avian pancreatic polypeptide is of this character and is described here. The results of the above attempts are both informative and promising.

An analogue of LHRH containing an extension of Gly-Cys at the carboxyl-terminus has been designed to permit reproducible coupling to a suitably modified carrier via a thioether bond. Potential energy calculations indicated that this analogue adopted a conformation in solution virtually identical to the type II′ turn around Gly-6—Leu-7 predicted for native LHRH. Intradermal administration of a conjugate of this analogue with purified protein derivative of tuberculin to male rats previously primed with BCG vaccine rapidly led to complete testicular regression. This adjuvant-free immunisation protocol may represent an alternative to castration for the veterinary control of reproductive function.

The molecular modelling of larger proteins benefits from a preliminary analysis of the sequence to identify regions of potential structural and functional importance. In this study the sequence of the epidermal growth factor receptor has been analysed using a variety of established methods and novel procedures developed for the study of weak internal and external homologies and for the use of homologous sequences in the prediction of secondary and super-secondary structures. The procedures explored here are potentially suitable for incorporation into an expert system for the initial investigation of protein sequence data.