Atkinson, C.E.; (2001) A novel approach to the rational design of artificial enzymes. Doctoral thesis , University of London.

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Abstract

This thesis describes a new approach to the rational design of an artificial esterase, and is in three parts. The first part of the thesis is an introduction to the design and synthesis of artificial enzymes. This details both traditional 'design', and more recent 'selection' approaches to artificial enzymes, and discusses the advantages and problems associated with the different strategies. The second part is a discussion of our investigations into the design and synthesis of polymeric artificial enzymes which are able to catalyse an ester hydrolysis. The research uses a novel strategy that combines the 'design' and 'selection' approaches: Using the concept of transition state theory, we aimed to design a unit that should bind and stabilise the transition state of a reaction. We then aimed to selectively incorporate this, and other catalytically active groups into a flexible, soluble polymer. The work starts with the synthesis of the ester substrate, and a phosphonate transition state analogue. The 'design' section of the project involved finding a low molecular weight 'binding unit' that could bind to the transition state analogue, and hence should bind and stabilise the transition state of our reaction. We decided to use dipeptides and studied binding using Pulsed Field Gradient NMR techniques to measure changes in diffusion coefficients. This is a technique which had previously only been used to study large molecule-small molecule binding. We successfully managed to apply this technique to studying small molecule-small molecule interactions, and thus it was found that the dipeptide arginine-arginine bound well to our transition state analogue, and the nature of the interactions were studied using molecular modelling. The 'selection' section involved incorporation of this unit into a polymer, along with the introduction of amino acids that could act as catalytically active groups. Both the dipeptide, and chosen amino acids were reacted with a polyallylamine backbone using standard peptide chemistry. The influences of the different polymers on the hydrolysis of the ester were investigated, and it was found that some of these polymers showed distinct catalytic 'enzyme like' properties. The results are reported within. The third section described the experimental work and procedure used throughout this thesis.

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