Molecular Interaction Fields Describing Halogen Bond Formable Areas on Protein Surfaces

Abstract

Molecular interaction fields (MIFs) are three-dimensional interaction maps that describe the intermolecular interactions expected to be formed around target molecules. In this paper, a method for the fast computation of MIFs using the approximation functions of quantum mechanics-level MIFs of small model molecules is proposed. MIF functions of N-methylacetamide with chlorobenzene, bromobenzene, and iodobenzene probes were precisely approximated and used to calculate the MIFs on protein surfaces. This method appropriately reproduced halogen-bond-formable areas around the ligand-binding sites of proteins, where halogen bond formation was suggested in a previous study.

Figure 1

Definition of the geometric parameters of halogen bonds. (a) Definitions of d(O–X), Θ₁(C–X–O), and Θ₂(X–O–C). (b) Definition of Ψ(N–C–O–X). (c) The molecular coordinate system (o-uvw) in relation to an amino acid residue. The w axis is defined along the C=O axis of an amino acid residue. The u axis is defined on the O=C–C_α plane perpendicular to the w axis. The v axis is perpendicular to the u and w axes. (d) The Θ₂(X–O–C) parameter in a spherical system; 180 – Θ₂ corresponds to the polar angle (θ). (d) The Ψ(N–C–O–X) parameter in a spherical system; 180 + Ψ corresponds to the azimuthal angle (ϕ).

Figure 2

Schematic of the MIF calculation procedure. (a) Definition of grid points around a target molecule. An N-methylacetamide molecule is used as the target. (b) Positioning of probe molecule on a grid point. A vector (G_n) is measured from the grid point to the carbonyl atom of the N-methylacetamide molecule. A molecular axis (M) is measured along the C-X bond of the probe molecule. (c) The probe molecule is rotated such that the molecular axis M coincides with vector G_n. (d) The interaction energy between N-methylacetamide and a probe molecule is estimated by a QM calculation. (e) MIF(QM, X) is obtained by repeating the procedures described in (b) to (d). The normalized MIF(QM, X) energies at the grid points are represented by spheres of distinct colors depending on the values. Orange spheres (≥0.8) are shown as an example.

Figure 3

(a) u, v, and w axes of the molecular coordinate in relation to the N-methylacetamide model. The w axis is defined along to the C=O axis of N-methylacetamide. The u axis is defined on the O=C–C plane of N-methylacetamide, perpendicular to the w axis. The v axis is perpendicular to the u and w axes. (b) x, y, and z axes of the laboratory coordinate and u, v, and w axes of the molecular coordinate defined on an amino acid residue.

Figure 4

MIFs(QM, X) of N-methylacetamide calculated using iodobenzene (left), bromobenzene (center), and chlorobenzene (right) probes. The MIF energy values were normalized by the most stable energy values. MIF(QM, Cl), MIF(QM, Br), and MIF(QM, I) values of 1.0 correspond to interaction energies of −1.89, −2.35, and −3.92 kcal/mol, respectively. 3D alternations of MIFs(QM, X) are depicted by spheres, color coded according to the MIF energy, while those of MIFs(func, X) are described by surface representation with according to the same color key.

Figure 5

(a) Ligand binding site of the aldose reductase (AR)/ligand (ZES) complex structure (PDB ID: 1IEI); the dashed line represents the formed O/Cl halogen bond. (b) The calculated MIF(func, Cl) for the ligand binding site of the AR structure. Halogen-bond-formable areas with halogen bond strengths of 0.8 or higher are shown as orange surfaces. (c) The superposition of the AR/ZES complex and calculated MIF(func, Cl).

Figure 6

(a) Ligand binding site of the cyclin-dependent kinase 2 (CDK2)/ligand (TBS) complex structure (PDB ID: 1P5E). The dashed line represent the three formed O/Br halogen bonds. (b) The calculated MIF(func, Br) for the ligand binding site of the CDK2 structure. Halogen-bond-formable areas with halogen bond strengths of 0.8 or higher are shown as orange surfaces. (c) The superposition of the CDK2/TBS complex and calculated MIF(func, Br).

Figure 7

(a) Ligand binding site of the transthyretin (TTR)/ligand (T44) complex structure (PDB ID: 1ETA). The dashed line represents the formed O/I halogen bond. (b) The calculated MIF(func, I) for the ligand binding site of the TTR structure. Halogen-bond-formable areas with halogen bond strengths of 0.8 or higher are shown as orange surfaces. (c) The superposition of the TTR/T44 complex and calculated MIF(func, I).

Figure 8

MIF(func, X) dependence on θ and φ for (a) MIF(func, Cl), (b) MIF(func, Br), (c and d) MIF(func, I). The 2D maps describe the MIF(func, X) energies when the d values are 3.0 Å for (a), (b), and (c), and 3.5 Å for (d). The θ (=180 – Θ₂) and φ (=180 + Ψ) values of each halogen bond investigated here were plotted on the 2D maps. The θ and φ values of the halogen bonds with strengths of 0.5 or higher are plotted in black. The θ and φ values of the halogen bonds with strengths lower than 0.5 are plotted in cyan.

Figure 9

Ligand binding site of the human serum albumin (HSA)/ligand (T44) complex structure (PDB ID: 1HK4). The calculated MIF(func, I) are shown by surface representations. (a) Halogen-bond-formable area with bond strengths of 0.8 or higher. (b) Halogen-bond-formable area with bond strengths of 0.3 or higher. The C–I/O halogen bond formed between the carbonyl oxygen of Asn429 and an iodine atom of T44 is represented by the dashed line. For simplicity, only the effect of Asn429 was evaluated in the MIF(func, I) calculation.