Key interactions of the mutant HIV-1 reverse transcriptase/efavirenz: an evidence obtained from ONIOM method

Abstract

Two-layered ONIOM calculations were performed in order to compare the binding of efavirenz (EFV) to the HIV-1 RT binding pocket of both wild type (WT) and K103N enzymes. The K103N mutation reduces the binding affinity of the inhibitor by 5.81 kcal mol À1 as obtained from the ONIOM2 (B3LYP/ 6-31G(d,p):PM3) method. These indicate that the loss of binding energy to K103N mutation can attribute to a weakened attractive interaction between the drug and residues surrounding in the binding pocket. The deformation of the K103N binding pocket requires more energy for structural rearrangement than that of the WT by approximately 4.0 kcal mol :1 . Moreover, the pairwise energies perfectly demonstrate that the K103N mutation affects on the loss of the interaction energy. In addition, the main influences are due to residues surrounding in the binding pocket; K101, K102, S105, V179, W229, P236 and E138. In particular, two residues; K101 and S105, established hydrogen bondings with the inhibitor. ONIOM calculations, resulting in the details of binding energy, interaction energy and deformation energy can be used to identify the key interaction and structural requirements of more potent HIV-1 RT inhibitor.

New Insights on the Molecular Recognition of Imidacloprid with Aplysia californica AChBP: A Computational Study

“…In the first, named ONIOM-1, the QM method was used to describe IMI, and the rest of the system was treated using QM′. The geometry optimizations were carried out within the backbone atoms fixed (BBF) approximation in which the geometries of both IMI and the lateral chains of the amino acids are fully optimized while the atomic positions of the polypeptide chain are frozen. ,, The minimum nature of the located stationary point was checked through a vibrational calculation (no imaginary frequencies). The geometries of IMI and each single residue in interaction were then extracted in order to compute the pairwise interaction energies, Δ E ( i , j ), through the two-body approach, normalΔ italicE ( i , j ) = italicE ( i , j ) − italicE ( i ) − italicE ( j ) + italicE false[ BSSE false] where E ( i , j ) is the energy of the IMI–residue pair, E ( i ) and E ( j ) are the energies of the isolated individual fragments, and E [BSSE] is the correction for the basis set superposition error (BSSE) computed through the counterpoise method (CP) .…”

“…The geometry optimizations were carried out within the backbone atoms fixed (BBF) approximation in which the geometries of both IMI and the lateral chains of the amino acids are fully optimized while the atomic positions of the polypeptide chain are frozen. 36,37,48 The minimum nature of the located stationary point was checked through a vibrational calculation (no imaginary frequencies). The geometries of IMI and each single residue in interaction were then extracted in order to compute the pairwise interaction energies, ΔE(i, j), through the two-body approach, 36…”

The ONIOM Method and Its Applications

“…Therefore, the water molecules induce the active-site conformation that enables the catalytic process and attract deoxyribonucleoside triphosphate to elongate the viral DNA during enzyme replication. The same group also studied interactions of saquinavir and HIV-1 protease with ONIOM­(B3LYP:­PM3:UFF), binding of efavirenz to HIV-1 RT and its mutated forms with ONIOM­(B3LYP:PM3:UFF), , binding of flurbiprofen to cyclooxygenase enzyme with ONIOM­(B3LYP:­PM3), IR spectra of volatile compounds from bread baking (acetaldehyde, acetylpyrazine, diacetyl, 2-ethyl-3-methylpyrazine, and acetylpyridine) and their interaction with a 703-atom model of bovine rhodopsin as a receptor with ONIOM­(B3LYP:PM3), and interactions of oxaloacetic acid with phosphoenolpyruvic carboxykinase in the presence and absence of hydrazine with ONIOM­(B3LYP:PM6) …”

Computational Screening of Phenylamino-Phenoxy-Quinoline Derivatives against the Main Protease of SARS-CoV-2 Using Molecular Docking and the ONIOM Method

“…In this study, SwissADME (Developed and maintained by the Molecular Modeling Group of the SIB, Swiss Institute of Bioinformatics, Lausanne, Switzerland) was applied to analyze the pharmacokinetic parameter of ligands [37]. Drug-likeness and molecular property prediction were screened depending on Lipinski's rule of five [25,26]. 8)) were used as ligands to study their binding interactions with the structure of M pro through molecular docking and the ONIOM method.…”

“…Molecular docking and the ONIOM method were used to describe the binding positions and binding interactions among biomolecules, and the results were presented as binding free energy and interaction energy values. Molecular docking and the ONIOM method have been successfully applied in most pharmaceutical research and modern drug discoveries [ 25 , 26 ]. Binding interactions are useful and important for understanding the function of the binding and inhibition processes.…”