324
X. Yang et al.
For many targets, there may be conserved hydrogen bonds. For example, three
residues involved in forming hydrogen bonds are particularly important for ligand
binding in ERα LBD, namely, Glu 353, Arg 394, and His 524. While in ERβ LBD,
the three residues were Glu 305, Arg 346, and His 475. Two residues (Gln 725
and Arg 766) formed conserved hydrogen bonds between the ligand and the human
progesterone receptor [93]. Forming the conserved hydrogen bonds network is the
critical factor triggering the subsequent active or inactive conformation transition
[94].
(3) Halogen bond
The halogen bond is a type of noncovalent interaction between a halogen atom (Cl,
Br, I) in one molecule and an electron donor (D = O, N, S) in another molecule
(Fig. 16.3b) [95]. The criteria for a halogen bond are:
(a) The distance between halogen atom and electron donor atom (d X···D ) is < their
sum of van der Waals radii;
(b) The C-X···D angle is >140° [96].
It was recognized that halogen bond plays important roles in the molecular recognition processes between organohalogens and target [91, 97, 98]. It has been reported
that many EDCs contained halogen moieties in their structure. For example, among
the 250 tested hTTR disruptors, 198 compounds (79%) were halogenated [99]. This
fact indicates that the hTTR disruptor halogen moieties may drive the interactions
between those compounds and hTTR. Indeed, our results implied that the halogen
moieties in hTTR binders could directly or indirectly affect the binding interactions
[100]. On one hand, the halogen atom could form halogen bonds and halogen–hydrogen bonds with the residues in hTTR directly. On the other hand, the halogen atom
could affect binding through inductive effects and hydrophobic effects. Additionally,
the results from Zhuang et al. [101] indicated that the bromine and chlorine atoms
in TBBPA, tribromobisphenol A (triBBPA), and tetrachlorobisphenol A (TCBPA)
could form halogen bonds with the residues in PPARγ (proliferator-activated receptor
gamma). The bromine atoms in Monobromobisphenol A (monoBBPA) and dibromobisphenol A (diBBPA) could form halogen bonds with the residues in ERα.
(4) Ionic interactions
An ionic interaction is formed between a charged group in the ligand and an oppositely charged group in the target. In some cases, a hydrogen bond would be superimposed onto an ionic interaction, which is called a charge-assisted hydrogen bond
[87]. If there exist stable ionic interactions, the distance between the two oppositely
charged groups is ≤5 Å [102]. For example, we analyzed the possibility of forming
an orientational ionic interaction between the model compounds (phenolic compounds and poly-/perfluorinated chemicals) and hTTR. We calculated the distance
(d) between the anionic groups in the ligands and the −NH 3
+ group in Lys 15 based
on the conformations from the simulation and the hTTR crystal structures. Among
the 82 simulated anionic ligands, there were 67 compounds with d ≤ 5 Å. For the 64
crystal complexes with anionic ligands, the d for 49 structures is ≤5 Å. The result
X. Yang et al.
For many targets, there may be conserved hydrogen bonds. For example, three
residues involved in forming hydrogen bonds are particularly important for ligand
binding in ERα LBD, namely, Glu 353, Arg 394, and His 524. While in ERβ LBD,
the three residues were Glu 305, Arg 346, and His 475. Two residues (Gln 725
and Arg 766) formed conserved hydrogen bonds between the ligand and the human
progesterone receptor [93]. Forming the conserved hydrogen bonds network is the
critical factor triggering the subsequent active or inactive conformation transition
[94].
(3) Halogen bond
The halogen bond is a type of noncovalent interaction between a halogen atom (Cl,
Br, I) in one molecule and an electron donor (D = O, N, S) in another molecule
(Fig. 16.3b) [95]. The criteria for a halogen bond are:
(a) The distance between halogen atom and electron donor atom (d X···D ) is < their
sum of van der Waals radii;
(b) The C-X···D angle is >140° [96].
It was recognized that halogen bond plays important roles in the molecular recognition processes between organohalogens and target [91, 97, 98]. It has been reported
that many EDCs contained halogen moieties in their structure. For example, among
the 250 tested hTTR disruptors, 198 compounds (79%) were halogenated [99]. This
fact indicates that the hTTR disruptor halogen moieties may drive the interactions
between those compounds and hTTR. Indeed, our results implied that the halogen
moieties in hTTR binders could directly or indirectly affect the binding interactions
[100]. On one hand, the halogen atom could form halogen bonds and halogen–hydrogen bonds with the residues in hTTR directly. On the other hand, the halogen atom
could affect binding through inductive effects and hydrophobic effects. Additionally,
the results from Zhuang et al. [101] indicated that the bromine and chlorine atoms
in TBBPA, tribromobisphenol A (triBBPA), and tetrachlorobisphenol A (TCBPA)
could form halogen bonds with the residues in PPARγ (proliferator-activated receptor
gamma). The bromine atoms in Monobromobisphenol A (monoBBPA) and dibromobisphenol A (diBBPA) could form halogen bonds with the residues in ERα.
(4) Ionic interactions
An ionic interaction is formed between a charged group in the ligand and an oppositely charged group in the target. In some cases, a hydrogen bond would be superimposed onto an ionic interaction, which is called a charge-assisted hydrogen bond
[87]. If there exist stable ionic interactions, the distance between the two oppositely
charged groups is ≤5 Å [102]. For example, we analyzed the possibility of forming
an orientational ionic interaction between the model compounds (phenolic compounds and poly-/perfluorinated chemicals) and hTTR. We calculated the distance
(d) between the anionic groups in the ligands and the −NH 3
+ group in Lys 15 based
on the conformations from the simulation and the hTTR crystal structures. Among
the 82 simulated anionic ligands, there were 67 compounds with d ≤ 5 Å. For the 64
crystal complexes with anionic ligands, the d for 49 structures is ≤5 Å. The result