Structure Function Correlation of G-Proteins

9808638 Warshel 该实验室开发的组合量子力学（从头算）/朗之万偶极子（QM(ai)/LD）模型将用于获得溶液中磷酸盐水解的可靠自由能表面。 本研究将重点通过重现现场主要实验结果来验证计算表面。 溶液反应经过验证和完善的势面将用于校准经验价键 (EVB) 势面，以研究蛋白质中的磷酸盐水解。 校准后的 EVB 表面将用于将溶液反应的能量插值到蛋白质环境中，并最终阐明 p21ras 的实际机制。将使用从头计算和 EVB 建模，以便从 G 蛋白及其过渡态类似物的新兴结构中提取更多独特的机制信息。 GTP 结合蛋白参与几乎所有生物体的细胞功能调节，并控制信号转导过程。 了解这些蛋白质的详细作用是分子生物学当前面临的重要挑战之一。 p21ras 和其他相关 G 蛋白的研究正在经历一场“结构革命”，G 蛋白及其与相应辅助蛋白的复合物的新结构正在迅速出现。 此外，有关 G 蛋白结构及其假设的过渡态 (TS) 类似物的令人兴奋的信息也正在变得可用。 这为阐明这些蛋白质作用的详细分子机制提供了独特的机会。 G 蛋白领域结构革命的持续为这些系统的计算机辅助结构功能分析提供了令人兴奋的机会。

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.