The aim of the research proposal is to study the biosynthesis and metabolism of oestrogen derivatives with state-of-the-art quantum mechanical (QM) and combined quantum mechanics molecular mechanics (QM/MM) calculations. Oestrogens play a manifold role in the correct functioning of the human body, which is especially pronounced in the case of women. Prolonged exposure to oestrogen has been shown to increase the risk of developing breast cancer due to the cumulative effect of toxic metabolites formed from oestrogens. State-of-the-art treatment of breast cancer involves inhibition of aromatase, the enzyme responsible for the last step of oestrogen biosynthesis. We intend to perform QM calculations to elucidate the factors that play a role in the cytochrome P450-dependant metabolism of oestrogens, and to rationalize the possible toxicity of oestrogen metabolites by assessing their proneness to autoxidation. Our second objective is to investigate the mechanism of the aromatization step of oestrogen biosynthesis. In order to do this we plan to carry out QM/MM calculations on the recently crystallized structure of aromatase and to investigate the feasibility of various reaction mechanisms. We expect that our results could significantly contribute to our present understanding to the functioning of this enzyme and could help in the development of the new generation of aromatase inhibitors to treat breast cancer. The research work is planned to be carried out at the HAS-BME Materials Structure and Modelling Research Group of the host institute (HAS-ORG). The European Reintegration Grant would aid the professional reintegration of Dr. Oláh to Hungary by allowing her to work independently. The grant would ensure (1) the transfer of knowledge that Dr. Oláh gained as a Marie Curie Research Fellow at the University of Bristol (UK) to Hungarian researchers (2) to develop a collaboration between the host institute and the University of Bristol.