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pH Dependence of Stability of the 10th Human Fibronectin Type III Domain:A Computational Study

机译：pH值依赖的第十个人类纤连蛋白III型域的稳定性：计算研究

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We present detailed computational studies based on electrostatic calculations to evaluate the origins of pK_a values and the pH dependence of stability for the 10th type III domain of human fibronectin(FNfnlO).One of our goals is to validate the calculation protocols by comparison to experimental data(Koide,A.;Jordan,M.R.;Horner,S.;Batori,V.;Koide,S.Biochemistry 2001,40,10326-10333).Another goal is to evaluate the sensitivity of the calculated ionization free energies and apparent pK_a values on local structural fluctuations,which do not alter the structural convergence to a particular architecture,by using a complete ensemble of solution NMR structures and the NMR average minimized structure of FNfnlO(Main,A.L.;Harvey,T.S.;Baron,M.;Boyd,J.;Campbell,I.D.Cell 1992,71,671-678).Our calculations demonstrate that,at high ionic strength,FNfnlO is more stable at low pH compared to neutral pH,in overall agreement with experimental data.This behavior is attributed to contributions from unfavorable Coulombic interactions in a surface patch for the pairs Asp7-Glu9 and Asp7-Asp23.The unfavorable interactions are decreased at low pH,where the acidic residues become neutral,and are further decreased at high ionic strength because of increased screening by salt ions.Elimination of the unfavorable interactions in the theoretical mutants Asp7Asn(D7N)and Asp7Lys(D7K)produce higher calculated stabilities at neutral pH and any ionic strength compared to the wild-type,in agreement with the experimental data.We also discuss subtleties in the calculated apparent pK_a values and ionization free energies,which are not in agreement with the experimental data.This work demonstrates that comparative electrostatic calculations can provide rapid predictions of pH-dependent properties of proteins and can be significant aids in guiding the design of proteins with tailored properties.
机译：我们在静电计算的基础上进行了详细的计算研究，以评估pK_a值的起源以及pH值对人纤连蛋白第10类III结构域（FNfn10）的稳定性的影响。我们的目标之一是通过与实验数据进行比较来验证计算方案（Koide，A。; Jordan，MR; Horner，S。; Batori，V。; Koide，S.Biochemistry 2001,40,10326-10333）。另一个目标是评估计算出的电离自由能和表观pK_a的灵敏度。通过使用溶液NMR结构和FNfn10的NMR平均最小化结构的完整集合（局部，结构波动不会改变结构收敛到特定体系结构）的值（Main，AL; Harvey，TS; Baron，M。; Boyd ，J。; Campbell，IDCell 1992,71,671-678）。我们的计算表明，与中性pH相比，在高离子强度下，FNfn10在低pH下比中性pH更稳定。这种行为归因于贡献来自不利Asp7-Glu9和Asp7-Asp23对在表面补丁中存在库仑相互作用。不利的相互作用在低pH时降低，其中酸性残基变为中性，而在高离子强度下由于盐离子增加的筛选而进一步降低。消除了理论突变体Asp7Asn（D7N）和Asp7Lys（D7K）的不利相互作用，与野生型相比，在中性pH和任何离子强度下产生了更高的计算稳定性，与实验数据相符。我们还讨论了计算中的细微差别表观pK_a值和电离自由能与实验数据不一致。这项工作表明，比较静电计算可以快速预测蛋白质的pH依赖特性，并且可以指导设计具有特定特性的蛋白质。 。

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