Koyama Yuka, Ueno-Noto Kaori, Takano Keiko
Department of Chemistry and Biochemistry, Graduate School of Humanities and Sciences, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
Center for Natural Sciences, College of Liberal Arts and Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan.
Comput Biol Chem. 2014 Apr;49:36-44. doi: 10.1016/j.compbiolchem.2014.01.013. Epub 2014 Feb 4.
In order to develop potential ligands to HIV-1 antibody 2G12 toward HIV-1 vaccine, binding mechanisms of the antibody 2G12 with the glycan ligand of D-mannose and D-fructose were theoretically examined. D-Fructose, whose molecular structure is slightly different from D-mannose, has experimentally shown to have stronger binding affinity to the antibody than that of D-mannose. To clarify the nature of D-fructose's higher binding affinity over D-mannose, we studied interaction between the monosaccharides and the antibody using ab initio fragment molecular orbital (FMO) method considering solvation effect as implicit model (FMO-PCM) as well as explicit water model. The calculated binding free energies of the glycans were qualitatively well consistent with the experimentally reported order of their affinities with the antibody 2G12. In addition, the FMO-PCM calculation elucidated the advantages of D-fructose over D-mannose in the solvation energy as well as the entropic contribution term obtained by MD simulations. The effects of explicit water molecules observed in the X-ray crystal structure were also scrutinized by means of FMO methods. Significant pair interaction energies among D-fructose, amino acids, and water molecules were uncovered, which indicated contributions from the water molecules to the strong binding ability of D-fructose to the antibody 2G12. These FMO calculation results of explicit water model as well as implicit water model indicated that the strong binding of D-fructose over D-mannose was due to the solvation effects on the D-fructose interaction energy.
为了开发针对HIV-1疫苗的HIV-1抗体2G12的潜在配体，从理论上研究了抗体2G12与D-甘露糖和D-果糖聚糖配体的结合机制。实验表明，分子结构与D-甘露糖略有不同的D-果糖对该抗体的结合亲和力比D-甘露糖更强。为了阐明D-果糖比D-甘露糖具有更高结合亲和力的本质，我们使用从头算片段分子轨道（FMO）方法研究了单糖与抗体之间的相互作用，该方法将溶剂化效应视为隐式模型（FMO-PCM）以及显式水模型。计算得到的聚糖结合自由能在定性上与实验报道的它们与抗体2G12的亲和力顺序良好一致。此外，FMO-PCM计算阐明了D-果糖在溶剂化能以及通过分子动力学模拟获得的熵贡献项方面相对于D-甘露糖的优势。还通过FMO方法仔细研究了在X射线晶体结构中观察到的显式水分子的影响。发现了D-果糖、氨基酸和水分子之间显著的对相互作用能，这表明水分子对D-果糖与抗体2G12的强结合能力有贡献。显式水模型以及隐式水模型的这些FMO计算结果表明，D-果糖比D-甘露糖具有更强的结合能力是由于对D-果糖相互作用能的溶剂化效应。
