The relevance of computer simulations in biochemistry and molecular biophysics is increasing. Accordingly, the proposal herein described is part of a regular research project already supported by FAPESP in order to consolidate a laboratory of Computational Biochemistry and Biophysics recently installed in the Institute of Chemistry in the University of Sao Paulo (IQ-USP). Here we will take advantage of the experience previously acquired by the proponent during her PhD with computer simulations and spectroscopical methods of membrane proteins to develop two lines of research that are part of the project mentioned above. In the first line, we propose to study the metalloprotein cytochrome bc1 , essential to photosynthetic and cellular respiration processes, and the electronic phenomena associated with one of its prosthetic groups, the Rieske-type [2Fe-2S] iron-sulfur cluster. We will first employ molecular mechanical computations to build a realistic model of cytochrome bc1 embeddedin lipid membranes and to probe the diffusion of its natural substrate, ubiquinone. Then, we will simulate the rate-limiting step of the catalysed Q-cycle with a hybrid potential of quantum chemistry and molecular mechanics (QC/MM). These detailed studies will shed bright light in the mechanism catalysed by cytochrome bc1. In the second line, we propose to investigate the role of protein intrinsic flexibility in molecular recognition. In particular, the Cdc25B phosphatase will be studied. This protein possesses a partially unfolded C-terminal. Cdc25B is also a target for the design of anti-neoplastic drugs.A combination of several spectroscopical data, including circular dichroism, infrared, fluorescence and X-ray scattering, will be acquired. These data will be compared in order to validate and guide computer simulations already under development in our laboratory that describe quantitatively the Cdc25B conformational states and recognition process. Although related to different subjects, the two lines of research proposed are linked by our continuous development of novel methodologies of computer simulations and the complementary usage of quantitative experimental measurements for their test and calibration.
News published in Agência FAPESP Newsletter about the scholarship: