The objective of this project is to obtain quantitative correlations between the structure and function of G-proteins. Obtaining a reliable detailed molecular description of the action of G-proteins can have a far reaching impact on the understanding key processes in the cell, by providing a more quantitative picture on the communication of information in the cell. Previous studies conducted in this project developed computer simulation methods to study GTP hydrolysis that is controlled by G-proteins. These simulations explored the key role of protein residues whose mutations lead to major change in activity and indicated that these residues act by modulating the coupling between the barrier for the chemical step and structural changes. This idea has been further validated by studies of the activation of the EF-Tu protein, which is involved in the elongation of the amino acid chain during protein synthesis. Attempts to confirm the above findings and to reach more unique conclusions involved systematic quantum mechanical ab initio studies of phosphate hydrolysis in solution, as well as a preliminary combined quantum (ab initio) / molecular mechanics (QM/MM) study of the activation of the protein Ras by the protein GAP. These studies reproduced key experimental findings while giving new insights into the nature of the free energy surface of the reaction. Further advances have been made in studying the conversion of chemical energy to work by the protein F1-ATPase and in studies of the unique unidirectional motions in this and in related systems. This project is placed now at a pivotal point, where it is poised to exploit the above progress and to move in parallel on the following fronts: (i) Further exploration of the activation of EF-Tu and the related protein EF-G , during the protein synthesis process. (ii) Continuing the studies of the chemical and conformational coupling in F1-ATPase. (iv) Exploring the action of G protein coupled receptors (GPCRs) which are responsible for the majority of cellular response to hormones and neurotransmitters. (iii) Conducting comparative studies of the action of different G-proteins and determining both the common and different catalytic factors (v) Exploring the information transfer in RasAGP and related systems by double mutations analysis (vi) Pushing for a consensus on the nature of the GTPase reactions by systematic ab initio QM/MM free energy calculations.
The advances in the above research will be integrated into teaching and training programs. The PI will develop a computer-modeling course for students. Movies that illustrate the process of cellular signal transduction and its molecular foundations will be produced. The movies will be distributed to high schools, where they should encourage young people to pursue research in this field.
