9808638 Warshel The combined Quantum Mechanical (ab initio)/ Langevin Dipoles (QM(ai)/LD) model developed in this laboratory will be used to obtain reliable free energy surfaces for phosphate hydrolysis in solution. This study will focus on validating the calculated surfaces by reproducing the main experimental results in the field. The validated and refined potential surfaces for the solution reaction will be used for calibrating Empirical Valence Bond (EVB) potential surfaces for studies of phosphate hydrolysis in proteins. The calibrated EVB surface will be used for interpolating the energetics of the solution reaction to protein environments and eventually for elucidating the actual mechanism of p21ras. Ab initio calculations and EVB modeling will be used in order to extract more unique mechanistic information from the emerging structure of G-proteins and their transition state analogs. GTP-binding proteins are involved in the regulation of cellular function in virtually all living organisms, and control signal transduction processes. Understanding the detailed actions of these proteins is one of the important current challenges of molecular biology. The studies of p21ras and other related G-proteins are undergoing a "structural revolution" from which new structures of G-proteins and their complexes with the corresponding accessory proteins are rapidly emerging. In addition, exciting information about the structure of G-proteins with their assumed transition state (TS) analogs is becoming available. This offers a unique opportunity for elucidating the detailed molecular mechanisms of the action of these proteins. The continuation of the structural revolution in the field of G-proteins provides an exciting opportunity for computer-aided structure-function analysis of these systems.
