Proton binding to proteins: A free-energy component analysis using a dielectric continuum model
Proton binding to proteins: A free-energy component analysis using a dielectric continuum model
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DOI：
10.1529/biophysj.104.055996
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发表时间：
2005-06-01
影响因子：
3.4
通讯作者：
Simonson, T
中科院分区：
文献类型：
--
作者：
Archontis, G;Simonson, T
质子结合在蛋白质结构和功能中起着至关重要的作用。我们报告了两种蛋白质中三种天冬氨酸的pK(a)计算，使用线性响应方法，以及“标准”泊松-玻尔兹曼方法。对质子结合反应的两个端点的构象进行平均，明确地模拟了蛋白质的原子自由度。从宏观上处理蛋白质的电子极化率和溶剂，得到了一个有意义的模型，没有可调的参数。定性地再现了静电势、质子结合自由能、马库斯重组自由能和溶剂分子动力学模拟的pK(a)位移，以及实验的pK(a)位移。对于具有较大pK(a)上移的硫氧还蛋白Asp-26，我们正确地捕获了不利于羧酸脱溶和与附近赖氨酸有利相互作用之间的平衡；同样，RNase A Asp-14也具有较大的pK(A)降移。对于未移位的硫氧还蛋白Asp-20，蛋白质空腔的脱溶被高估了2.9 pK(a)单位；有几个效应可以解释这一点。“标准”泊松-玻尔兹曼方法通过使用一个大的、特殊的蛋白质介电体来回避这个问题；但是蛋白质的电荷-电荷相互作用被错误地缩小了，给出了一个不平衡的反应描述，并且对Asp-26和Asp-14的位移的pK(a)值有很大的误差。
Proton binding plays a critical role in protein structure and function. We report pK(a) calculations for three aspartates in two proteins, using a linear response approach, as well as a "standard'' Poisson-Boltzmann approach. Averaging over conformations from the two endpoints of the proton-binding reaction, the protein's atomic degrees of freedom are explicitly modeled. Treating macroscopically the protein's electronic polarizability and the solvent, a meaningful model is obtained, without adjustable parameters. It reproduces qualitatively the electrostatic potentials, proton-binding free energies, Marcus reorganization free energies, and pK(a) shifts from explicit solvent molecular dynamics simulations, and the pK(a) shifts from experiment. For thioredoxin Asp-26, which has a large pK(a) upshift, we correctly capture the balance between unfavorable carboxylate desolvation and favorable interactions with a nearby lysine; similarly for RNase A Asp-14, which has a large pK(a) downshift. For the unshifted thioredoxin Asp-20, desolvation by the protein cavity is overestimated by 2.9 pK(a) units; several effects could explain this. 'Standard'' Poisson-Boltzmann methods sidestep this problem by using a large, ad hoc protein dielectric; but protein charge-charge interactions are then incorrectly downscaled, giving an unbalanced description of the reaction and a large error for the shifted pK(a) values of Asp-26 and Asp-14.