Computational Study of Halogen Bonding On The Structural Stability of Proteins

Background

The charge distribution around covalently bound halogen atoms is anisotropic, and halogen bonds are important noncovalent interactions in molecular recognition and drug design. In drug design, existing studies have mainly focused on the halogen bonding between halogen-containing small molecule compounds and target proteins. Recently, some researchers have investigated the halogen bonds in proteins/peptides based on statistical analysis of databases and combined with quantum chemical calculations and molecular dynamics simulations, and found that halogen bonds at the protein-peptide interaction interface can enhance their binding affinity, and that intramolecular halogen bonds formed within proteins help to increase the structural stability of proteins, whereas those that do not can lead to a decrease in their structural stability will be reduced for proteins that cannot form intramolecular halogen bonds.

Introduction

The researchers first screened 195,093 three-dimensional structures in the PDB database and found that halogenated bonds formed by halogenated proteins or halogenated peptides are mainly found at protein-peptide interaction interfaces (inter_XBs) as well as inside protein structures (intra_XBs) (Figure 2a). Statistical analysis revealed that side-chain atoms (nitrogen and oxygen) were more likely to act as halogen bond acceptors than main-chain atoms (Fig. 2b), whereas in halogen bonds formed by proteins with small-molecule compounds, this trend was not evident

Disscusion

For the halogen bond between protein-polypeptide, the researchers confirmed the formation of a strong halogen bond between the protein-halogenated polypeptide complexes through QM/MM structure optimization, natural bond orbital (NBO) theory and independent gradient model (IGM) analysis (Figure 3). To further investigate the role of halogen bonds on protein-peptide binding, the researchers performed binding energy calculations on the optimized structures of the protein-peptide complexes before and after halogenation, and the results showed that the presence of halogen bonds significantly enhanced the protein-peptide binding (Table I).

Table I. Protein-peptide binding energies before and after halogen-containing

The researchers further calculated the difference in local interaction time (LIT) of the protein amino acids before and after halogenation (ΔLIT = LITX-LITnoX), and the results showed that the introduction of halogen also affects the degree of contact between the amino acid residues (Fig. 4), which is supposed to be an important factor affecting the stability. For example, in the 2ZXV system, where intramolecular halogen bonds were formed, the researchers observed that the degree of contact between amino acid residues was enhanced after halogenation, while in the 5KI8 system, where no intramolecular halogen bonds were formed, the degree of contact between residues was weakened after halogenation.

Figure 4. Radius of gyration distributions of proteins before and after halogenation. x indicates that the protein contains halogen, and noX indicates that the protein does not contain halogen.

This paper elucidates for the first time the nature of halo-bonding interactions, reveals that intermolecular forces such as halo-bonding are generally underestimated in the PDB database, and finds for the first time that nucleic acids can also act as halo-bonding receptors.

Related Service We Offer