Structure Function Correlation of G-Proteins

9808638 Warshel本实验室建立的量子力学(从头算)/朗之万偶极子(QM(Ai)/Ld)组合模型将被用来获得溶液中磷酸盐水解的可靠自由能表面。这项研究将集中于通过重现现场的主要实验结果来验证计算表面。经过验证和改进的溶液反应势面将用于校准经验价键(EVB)势面，用于研究蛋白质中的磷酸水解。校准后的EVB表面将用于对蛋白质环境中溶液反应的能量学进行插补，最终用于阐明p21ras的实际机制。为了从G蛋白及其过渡态类似物的新结构中提取更多独特的机制信息，将使用从头计算和EVB模拟。GTP结合蛋白参与调节几乎所有生物的细胞功能，并控制信号转导过程。了解这些蛋白质的详细作用是当前分子生物学面临的重要挑战之一。对p21ras和其他相关G蛋白的研究正在经历一场“结构革命”，新的G蛋白结构及其与相应辅助蛋白的复合体正在迅速涌现。此外，有关G蛋白及其假定的过渡态(TS)类似物的结构的令人兴奋的信息正在变得可用。这为阐明这些蛋白质作用的详细分子机制提供了一个独特的机会。G蛋白领域结构革命的继续为这些系统的计算机辅助结构功能分析提供了一个令人兴奋的机会。

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.