Lima Neto José X, Fulco Umberto L, Albuquerque Eudenilson L, Corso Gilberto, Bezerra Eveline M, Caetano Ewerton W S, da Costa Roner F, Freire Valder N
Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal-RN, Brazil.
Phys Chem Chem Phys. 2015 May 21;17(19):13092-103. doi: 10.1039/c4cp05630b.
We employ quantum biochemistry methods based on the Density Functional Theory (DFT) approach to unveil the detailed binding energy features of willardiines co-crystallized with the AMPA receptor. Our computational results demonstrate that the total binding energies of fluorine-willardiine (FW), hydrogen-willardiine (HW), bromine-willardiine (BrW) and iodine-willardiine (IW) to the iGluR2 ligand-pocket correlate with the agonist binding energies, whose experimental sequential data match our computational counterpart, excluding the HW case. We find that the main contributions to the total willardiine-iGluR2 binding energy are due to the amino acid residues in decreasing order Glu705 > Arg485 > Ser654 > Tyr450 > T655. Furthermore, Met708, which is positioned close to the 5-substituent, attracts HW and FW, but repels BrW and IW. Our results contribute significantly to an improved understanding of the willardiine-iGluR2 binding mechanisms.
我们采用基于密度泛函理论（DFT）方法的量子生物化学方法，以揭示与AMPA受体共结晶的威拉地丁的详细结合能特征。我们的计算结果表明，氟代威拉地丁（FW）、氢代威拉地丁（HW）、溴代威拉地丁（BrW）和碘代威拉地丁（IW）与离子型谷氨酸受体2（iGluR2）配体口袋的总结合能与激动剂结合能相关，除HW情况外，其实验顺序数据与我们的计算结果相符。我们发现，对威拉地丁-iGluR2总结合能的主要贡献来自氨基酸残基，其贡献顺序为Glu705 > Arg485 > Ser654 > Tyr450 > T655。此外，位于5-取代基附近的Met708吸引HW和FW，但排斥BrW和IW。我们的结果对深入理解威拉地丁-iGluR2结合机制有显著贡献。
