A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors

• Published in: Physical chemistry chemical physics : PCCP Vol. 17; no. 19; pp. 13092 - 13103
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England 21.05.2015
• Subjects: Alanine - analogs & derivatives; Alanine - metabolism; Alanine - pharmacology; Amino acids; Binding energy; Biochemistry; Computation; Density functional theory; Drug Partial Agonism; Ligands; Models, Molecular; Physical chemistry; Protein Conformation; Quantum Theory; Receptors; Receptors, AMPA - agonists; Receptors, AMPA - chemistry; Receptors, AMPA - metabolism; Residues; Thermodynamics; Uracil - metabolism; Uracil - pharmacology
• ISSN: 1463-9076; 1463-9084
• 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.