Polarization and Polarizability Assessed by Protein Amide Acidity
Polarization and Polarizability Assessed by Protein Amide Acidity
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DOI：
10.1021/bi900526z
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发表时间：
2009-07-14
期刊：
影响因子：
2.9
通讯作者：
LeMaster, David M.
中科院分区：
文献类型：
--
作者：
Hernandez, Griselda;Anderson, Janet S.;LeMaster, David M.
确定了 FK506 结合蛋白 (FKBP12)、泛素和胰凝乳蛋白酶抑制剂 2 (CI2) 的酰胺的氢氧化物催化交换速率常数，这些酰胺在高分辨率 X 射线结构中是溶剂可及的。结合之前来自激烈火球菌的红氧还蛋白的氢交换结果，通过连续介电方法计算这些酰胺的酸度，作为不可极化静电参数集、内部介电常数和肽阴离子电荷分布的函数。对于 10(0.67) 至 10(9.0) M-1 s(-1) 范围内的 56 个酰胺交换速率常数，使用内部介电值 3 和从头算导出的阴离子电荷分布的 CHARMM22 参数集得出的 rmsd 值为 7。 OPLS-AA 参数集产生了相对稳健的预测，而 PARSE、AMBER parm99 和 AMBER ff03 的预测表现较差。最佳内部介电值较小，加上肽阴离子中间体的短暂寿命以及预测和观察到的酰胺酸度之间相关性的均匀性，与电子极化率一致，为介电屏蔽提供了主要贡献。通过构造，不可极化力场不会通过电子极化率来模拟电场衰减。当 epsilon(tau) 设置为真空介电值 1 时，通过这种力场准确预测总静电能量需要原子电荷值的超极化，以便与平均电场能量密度 (1/2)epsilon(tau)E-2(tau) 相匹配。实验氢交换数据的最终预测表明，当忽略由于电子极化而导致的电介质屏蔽时，可能会出现预测静电势的重大系统误差。
Hydroxide-catalyzed exchange rate constants were determined for those amides of FK506-binding protein (FKBP12), ubiquitin, and chymotrypsin inhibitor 2 (CI2) that are solvent-accessible in the high-resolution X-ray structures. When combined with previous hydrogen exchange results for the rubredoxin from Pyrococcus furiosus, the acidity of these amides was calculated by continuum dielectric methods as a function of the nonpolarizable electrostatic parameter set, internal dielectric, and the charge distribution of the peptide anion. The CHARMM22 parameter set with an internal dielectric value of 3 and an ab initio-derived anion charge distribution yielded an rmsd value of 7 for the 56 amide exchange rate constants ranging from 10(0.67) to 10(9.0) M-1 s(-1). The OPLS-AA parameter set yielded comparably robust predictions, while that of PARSE, AMBER parm99, and AMBER ff03 performed more poorly. The small value for the optimal internal dielectric, combined with the brief lifetime of the peptide anion intermediate and the uniformity of the correlation between predicted and observed amide acidities, is consistent with electronic polarizability providing the dominant contribution to dielectric shielding. By construction, nonpolarizable force fields do not model electric field attenuation by electronic polarizability. Accurate prediction of the total electrostatic energy by such force fields necessitates the hyperpolarization of the atomic charge values in order to match the average electric field energy density (1/2)epsilon(tau)E-2(tau) when epsilon(tau) is set to the in vacuo dielectric value of 1. The resulting predictions of the experimental hydrogen exchange data demonstrate the substantial systematic errors in the predicted electrostatic potential that can arise when dielectric shielding due to electronic polarizability is neglected.