Computational Analysis of the Interaction Energies between Amino Acid Residues of the Measles Virus Hemagglutinin and Its Receptors

Abstract

Measles virus (MV) causes an acute and highly devastating contagious disease in humans. Employing the crystal structures of three human receptors, signaling lymphocyte-activation molecule (SLAM), CD46, and Nectin-4, in complex with the measles virus hemagglutinin (MVH), we elucidated computationally the details of binding energies between the amino acid residues of MVH and those of the receptors with an ab initio fragment molecular orbital (FMO) method. The calculated inter-fragment interaction energies (IFIEs) revealed a number of significantly interacting amino acid residues of MVH that played essential roles in binding to the receptors. As predicted from previously reported experiments, some important amino-acid residues of MVH were shown to be common but others were specific to interactions with the three receptors. Particularly, some of the (non-polar) hydrophobic residues of MVH were found to be attractively interacting with multiple receptors, thus indicating the importance of the hydrophobic pocket for intermolecular interactions (especially in the case of Nectin-4). In contrast, the electrostatic interactions tended to be used for specific molecular recognition. Furthermore, we carried out FMO calculations for in silico experiments of amino acid mutations, finding reasonable agreements with virological experiments concerning the substitution effect of residues. Thus, the present study demonstrates that the electron-correlated FMO method is a powerful tool to search exhaustively for amino acid residues that contribute to interactions with receptor molecules. It is also applicable for designing inhibitors of MVH and engineered MVs for cancer therapy.

Fragment Molecular Orbital Based Interaction Analyses on COVID-19 Main Protease - Inhibitor N3 Complex (PDB ID:6LU7)

“…The second term in this equation corresponds to pair interaction energy (PIE) [9] or inter-fragment interaction energy (IFIE) [10,23], which is quite useful for interaction analyses [8,10] (See Refs [11][12][13][14][15][16][17] when necessary). We therefore used IFIE for the interaction analysis in this paper.…”

Identification of amino acid residues involved in the interaction between peste-des-petits-ruminants virus haemagglutinin protein and cellular receptors

“…The suggestion that the mutated amino acids (I61P, H62A, I210P A211R, S226A and R227A) in mSLAM1 have a crucial role in PPRV H binding to SLAM is in agreement with previous findings [ 14, 29–31 ]. Computational analysis showed that K77 and E123 in human and canine SLAM play pivotal roles in binding to the H protein of MV and CDV [ 16, 42, 43 ]. The two residues are known to be well conserved among the reported mammalian SLAMs.…”

<b>Development of an automated fragment molecular orbital (FMO) calculation protocol toward construction of quantum mechanical </b><b>calculation database for large biomolecules </b>

“…The FMO method is already recognized as a useful drug design tool to analyze ligand binding interactions, incorporating electrostatic interactions such as hydrogen bonds and dispersion forces such as CH/π interactions, using the pair interaction energy decomposition analysis (PIEDA) [4,5] and fine fragmentation by the functional group unit, rather than the amino acid residue unit and the whole ligand [6][7][8]. Recently, the IFIE analysis and its energy decomposition analysis have been applied to the prediction of binding affinity for rational drug design [9][10][11][12][13][14][15][16][17][18]. Using FMO calculations of tens of complexes for one target protein, the essential and characteristic interactions of the ligand binding mode can be abstracted from the IFIE and PIEDA data by clustering methods [19][20] and singular value decomposition [21].…”