利用坐标耦合自由能微扰法探究二氢叶酸还原酶 - 甲氨蝶呤复合物中的盐桥。
Probing the salt bridge in the dihydrofolate reductase-methotrexate complex by using the coordinate-coupled free-energy perturbation method.
作者信息
Singh U C
机构信息
Department of Molecular Biology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
出版信息
Proc Natl Acad Sci U S A. 1988 Jun;85(12):4280-4. doi: 10.1073/pnas.85.12.4280.
Abstract
The importance of the ionic interaction due to the formation of the salt bridge between the Asp-27 and the pteridine ring in Escherichia coli dihydrofolate reductase-methotrexate complex has been studied by using the free-energy perturbation method. The calculation suggests that the ion-pair contribution to the binding energy is insignificant, as the enzyme surroundings do not stabilize the salt bridge to the extent of the desolvation of the charged groups. The activation barrier for the proton exchange between the pteridine ring and the Asp-27 is calculated to be 20.1 kcal/mol (1 cal = 4.184 J) by using the coordinate-coupled perturbation method, implying that this may be a channel to the proton exchange from the pteridine ring to the solvent. The Gibbs-energy difference of binding between the Asn-27 and Ser-27 is calculated to be 3.2 kcal/mol and is mainly due to the electrostatic interactions.
摘要
通过使用自由能微扰方法，研究了大肠杆菌二氢叶酸还原酶 - 甲氨蝶呤复合物中Asp - 27与蝶啶环之间形成盐桥所导致的离子相互作用的重要性。计算表明，离子对结合能的贡献微不足道，因为酶周围环境对盐桥的稳定程度不足以使带电基团去溶剂化。使用坐标耦合微扰方法计算得出，蝶啶环与Asp - 27之间质子交换的活化能垒为20.1千卡/摩尔（1卡 = 4.184焦耳），这意味着这可能是质子从蝶啶环交换到溶剂的一个通道。计算得出Asn - 27和Ser - 27之间结合的吉布斯自由能差为3.2千卡/摩尔，主要是由于静电相互作用。
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本文引用的文献
1
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Biochemistry. 1981 Jul 7;20(14):3972-8. doi: 10.1021/bi00517a005.
2
3
Protonated state of methotrexate, trimethoprim, and pyrimethamine bound to dihydrofolate reductase.与二氢叶酸还原酶结合的甲氨蝶呤、甲氧苄啶和乙胺嘧啶的质子化状态。
Arch Biochem Biophys. 1983 Oct 15;226(2):567-77. doi: 10.1016/0003-9861(83)90326-0.
4
The pH-dependence of the binding of dihydrofolate and substrate analogues to dihydrofolate reductase from Escherichia coli.
Biochim Biophys Acta. 1983 Jun 29;745(3):247-58. doi: 10.1016/0167-4838(83)90056-0.
5
Spectral changes associated with binding of folate compounds to bacteriophage T4 dihydrofolate reductase.
J Biol Chem. 1972 Sep 25;247(18):5661-7.
6
Deaza aalogues of amethopterin (methotrexate).
Ann N Y Acad Sci. 1971 Nov 30;186:227-34. doi: 10.1111/j.1749-6632.1971.tb46976.x.
7
Calculation of the relative change in binding free energy of a protein-inhibitor complex.蛋白质-抑制剂复合物结合自由能相对变化的计算。
Science. 1987 Jan 30;235(4788):574-6. doi: 10.1126/science.3810157.
8
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9
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