THEORETICAL STUDIES OF PROTEIN ELECTROSTATICS

这项研究项目的广泛目标是表征和计算蛋白质中的静电效应。将使用一个半连续的静电模型，在该模型中，蛋白质被视为包含嵌入电荷的低介电体，浸入高介电介质中。蛋白质结构的原子坐标和半径决定了介电边界的形状，而介电边界通常是复杂和不规则的，所产生的静电方程是用有限数值技术求解的。将开发一些方法来考虑蛋白质pH滴定中构象灵活性的影响，以及pH驱动的构象变化。静电模型还将与更详细的量子力学计算相结合，以描述蛋白质的活性部位。这些方法将被用于研究蛋白质酪氨酸磷酸酶，一类参与细胞生长和分化调节的酶；以及细菌视紫红质，一种光驱动的质子泵。蛋白质酪氨酸磷酸酶必须在催化途径的过渡态稳定一个大的负电荷，并具有几个具有异常大的功能或结构重要性的PKA移位的可电离侧链。在细菌视紫红质中，在其光周期中，分子内几个pKa值和质子转移能量的调节对于其作为质子泵的功能是至关重要的。

The broad objective of this research project is to characterize and calculate electrostatic effects in proteins. A semi-continuum electrostatic model will be used, in which the protein is treated as a low-dielectric object containing embedded charges immersed in a high-dielectric solvent. The atomic coordinates and radii of the protein structure determine the shape of the dielectric boundary, which is generally complex and irregular, and the resulting electrostatic equations are solved by finite numerical techniques. Methods will developed to account for the effects of conformational flexibility in the pH titration of proteins, and pH-driven conformational change. The electrostatic model will also be combined with more detailed quantum mechanical calculations for the description of protein active sites. These methods will be applied to studies of the protein tyrosine phosphatases, a class of enzymes involved in the regulation of cell growth and differentiation; and to bacteriorhodopsin, a light-driven proton pump. The protein tyrosine phosphatases must stabilize a large negative charge in a transition state of the catalytic pathway, and have several ionizable sidechains with unusually large pKa shifts of functional or structural importance. In bacteriorhodopsin, the modulation of several pKa values and proton transfer energies within the molecule during its photocycle is crucial to its function as a proton pump.