Molecular Dynamics Simulation Investigation of the Binding and Interaction of the EphA6–Odin Protein Complex

Abstract

Protein–protein interaction plays an important role in the development of almost all cells. Elucidating the dynamic binding and affinity of a protein–protein complex is essential for understanding the biological functions of proteins. EphA6 and Odin proteins are members of the Eph (erythropoietin-producing hepatocyte) receptor family and the Anks (ankyrin repeat and sterile α motif domain-containing) family, respectively. Odin significantly functions in regulating endocytosis, degradation, and stability of EphA receptors. In this work, the key residues of the interaction interface were determined through a hydrogen bond, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and dynamic correlation analysis of the conventional molecular dynamics (MD) simulations. The calculated standard binding free energy, −7.92 kcal/mol, between EphA6 and Odin is quite consistent with the experimental measurement value, −8.73 kcal/mol. By the combination of several MD simulation techniques, our investigation of the binding process reveals the detailed representative characteristics of the entire binding pathway at the molecular level. Based on the obtained potential of the mean force (PMF) curve, the analysis of the simulation trajectories shows that the residue Arg1013 in the receptor EphA6 is responsible for capturing Asp739 and Asp740 in the ligand Odin during the initial stage of binding. In the later stage of binding, the hydrogen bonds and salt bridges between a series of residues Lys973, Leu1007, Gly1009, His1010, and Arg1012 in the receptor and residues Leu735, Asn736, Asp739, Asp740, and Asp753 in the ligand mainly contribute to the stability of the protein complex. In addition, the specific change process of the receptor–ligand-binding mode is also clarified during the binding process. Our present simulation will promote a deep understanding of the protein–protein interaction, and the identified key interresidue interaction will be theoretical guidance for the design of protein drugs.

The molecular mechanism of non-covalent inhibitor WU-04 targeting SARS-CoV-2 3CLpro and computational evaluation of its effectiveness against mainstream coronaviruses

“…In addition, to investigate the effect of WU-04 binding on the correlation of protein residues, the dynamic cross-correlation matrix (DCCM) analysis was implemented. 53,54 As shown in Fig. 5B, significant distinctions are observed between the two systems as a whole.…”

Computational Design of Miniprotein Inhibitors Targeting SARS-CoV-2 Spike Protein

“…In order to further investigate the conformational changes and the correlation in the movement of protein residues after inhibitor mutation, dynamic cross-correlation matrix (DCCM) analysis was performed on the basis of Cα atoms throughout the MD simulation (see Figure and Figure S6 in the Supporting Information (replica simulation)). In the figure, the dense color regions represent the respective positive and negative correlation motion between the protein residues, in which the correlation motions (highly positive) of residues are represented as cyan color regions, whereas the anticorrelation motions (highly negative) of residues are represented as magenta color regions . The uncolored regions indicate no correlation in the movement of protein residues.…”

“…In the figure, the dense color regions represent the respective positive and negative correlation motion between the protein residues, in which the correlation motions (highly positive) of residues are represented as cyan color regions, whereas the anticorrelation motions (highly negative) of residues are represented as magenta color regions. 76 The uncolored regions indicate no correlation in the movement of protein residues. The highly correlated motions mean the strong interaction of the inhibitor and its mutants with the RBD binding sites, resulting in coordinated movement of the entire structure.…”

In silico design of miniprotein to inhibit SARS-CoV-2 variant Omicron spike protein

“…The length and direction of the yellow arrows in the figure represent the strength and direction of the motion, respectively. 63 It can be seen that in the initial inhibitor AHB2 complex system, the residues at the interaction interface of the inhibitor AHB2 with the RBD O protein show a slight movement (Fig. 8(A)).…”