DeChancie Jason, Houk K N
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, USA.
J Am Chem Soc. 2007 May 2;129(17):5419-29. doi: 10.1021/ja066950n. Epub 2007 Apr 7.
The unusually strong reversible binding of biotin by avidin and streptavidin has been investigated by density functional and MP2 ab initio quantum mechanical methods. The solvation of biotin by water has also been studied through QM/MM/MC calculations. The ureido moiety of biotin in the bound state hydrogen bonds to five residues, three to the carbonyl oxygen and one for each--NH group. These five hydrogen bonds act cooperatively, leading to stabilization that is larger than the sum of individual hydrogen-bonding energies. The charged aspartate is the key residue that provides the driving force for cooperativity in the hydrogen-bonding network for both avidin and streptavidin by greatly polarizing the urea of biotin. If the residue is removed, the network is disrupted, and the attenuation of the energetic contributions from the neighboring residues results in significant reduction of cooperative interactions. Aspartate is directly hydrogen-bonded with biotin in streptavidin and is one residue removed in avidin. The hydrogen-bonding groups in streptavidin are computed to give larger cooperative hydrogen-bonding effects than avidin. However, the net gain in electrostatic binding energy is predicted to favor the avidin-bicyclic urea complex due to the relatively large penalty for desolvation of the streptavidin binding site (specifically expulsion of bound water molecules). QM/MM/MC calculations involving biotin and the ureido moiety in aqueous solution, featuring PDDG/PM3, show that water interactions with the bicyclic urea are much weaker than (strept)avidin interactions due to relatively low polarization of the urea group in water.
已通过密度泛函和MP2从头算量子力学方法研究了抗生物素蛋白和链霉抗生物素蛋白与生物素异常强烈的可逆结合。还通过QM/MM/MC计算研究了生物素在水中的溶剂化作用。处于结合状态的生物素的脲基部分与五个残基形成氢键，其中三个与羰基氧形成氢键，每个-NH基团各形成一个氢键。这五个氢键协同作用，导致稳定化作用大于各个氢键结合能之和。带电荷的天冬氨酸是关键残基，它通过极大地极化生物素的尿素，为抗生物素蛋白和链霉抗生物素蛋白的氢键网络中的协同作用提供驱动力。如果去除该残基，网络就会被破坏，相邻残基能量贡献的减弱会导致协同相互作用显著降低。在链霉抗生物素蛋白中，天冬氨酸直接与生物素形成氢键，在抗生物素蛋白中则相隔一个残基。计算得出，链霉抗生物素蛋白中的氢键基团比抗生物素蛋白具有更大的协同氢键效应。然而，由于链霉抗生物素蛋白结合位点去溶剂化的代价相对较大（特别是结合水分子的排出），预计静电结合能的净增加有利于抗生物素蛋白-双环尿素复合物。涉及生物素和水溶液中脲基部分的QM/MM/MC计算（采用PDDG/PM3）表明，由于水中尿素基团的极化程度相对较低，水与双环尿素的相互作用比（链霉）抗生物素蛋白的相互作用弱得多。
