THEORETICAL STUDIES OF PROTEIN ELECTROSTATICS

该研究项目的主要目标是表征和计算蛋白质中的静电效应。 一个半连续静电模型将被使用，其中的蛋白质被视为一个低介电的对象包含嵌入的电荷浸没在一个高介电溶剂。 蛋白质结构的原子坐标和半径决定了介电边界的形状，介电边界通常是复杂和不规则的，并且由此产生的静电方程通过有限数值技术求解。 将开发的方法来解释蛋白质的pH滴定中的构象灵活性的影响，和pH驱动的构象变化。 静电模型也将结合更详细的量子力学计算的蛋白质活性位点的描述。 这些方法将被应用于蛋白质酪氨酸磷酸酶的研究，这是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中稳定大的负电荷，并且具有几个具有功能或结构重要性的异常大的pKa位移的可电离侧链。 在细菌视紫红质中，在其光循环期间分子内的几个pKa值和质子转移能量的调制对其作为质子泵的功能至关重要。

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.