Computer simulation of metalloenzymes and of flexible proteins

Abstract

Computer simulation has increasing presence and importance for research in chemistry, biochemistry and molecular biophysics. A clear recognition of this research area was the Nobel prize in Chemistry awarded in 2013 for the development of hybrid methods in molecular simulation.The research proposal presented here will be conducted in the Computational Biochemistry and Biophysics laboratory installed in the Instituto de Química at the Universidade de São Paulo (IQ-USP) and will be carried out by four graduate students already members of the laboratory, besides the principal investigator and foreign collaborators. On this project, we propose to continue our recent developments and applications of innovative methods in molecular simulation to study proteins involved in bio-energetical processes and in molecular recognition.We will investigate the reaction mechanisms of metalloenzymes containing iron-sulfur clusters found in the mitochondrial electron transfer chain and in bacteria. Redox reactions of their substrates, ubiquinone, and of the iron-sulfur clusters in complexes I, II and III will be simulated with atomistic detail and a description by a hybrid potential of quantum chemistry and molecular mechanics (QC/MM). Approximations proposed and implements by our group to study metalloproteins will be used. We also propose to continue the investigation of the forced unfolding of rubredoxin, a simple iron-sulfur protein, in comparison with atomic force microscopy (AFM) experiments to understand its mechanical properties and stability of Fe-S bonds.We will also continue the characterization of the structural flexibility and the complexation to small molecule ligands of the human phosphatase Cdc25B, that is a possible target for the development of antineoplastic inhibitors. Here we will combine molecular simulation with spectroscopical experiments to identify transient states in the flexible C-terminal region and its role in the complexation to ligands. (AU)