Binding Mode of the Heterocyclic Amine 2-Amino-9H-pyrido[2,3-b] indole (AαC) to DNA Elucidated by Molecular Docking and Molecular Dynamics Simulation
Abstract
Background: 2-Amino-9H-pyrido[2,3-b]indole (AαC) is a mutagenic and carcinogenic heterocyclic aromatic amine formed by pyrolysis of proteins in cooked meat and present in tobacco smoke. After metabolic activation to a reactive nitrenium ion, it modifies DNA covalently, mainly at guanine. How AαC first associates with DNA, before any covalent bond forms, is not well understood. Methods: We docked AαC to three B-DNA dodecamers (PDB IDs 1BNA, 2Z2G and 2HKC) with PatchDock and FireDock, and ran explicit-solvent molecular dynamics (MD) simulations of the docked complexes in NAMD 2.13 with the CHARMM36 force field (1BNA: 10 ns; 2Z2G: 50 ns; NPT, 300 K, 0.15 M NaCl). Results: AαC bound in the minor groove of all three dodecamers, with global binding energies of -50.08 (1BNA), -53.41 (2Z2G) and -45.22 kcal/mol (2HKC). Atomic van der Waals terms contributed -16.41 to -18.36 kcal/mol, and single hydrogen bonds to thymine, guanine or adenine oxygen atoms were identified (2.2–2.8 Å). In the simulations AαC remained bound with a low, stable backbone RMSD, whereas the DNA backbone fluctuated considerably more. The minor-groove poses were poorly oriented for covalent attack when the base pairs were intact and canonical. Conclusions: Neutral AαC forms stable, groove-bound non-covalent complexes with B-DNA, but these complexes do not by themselves position the amine for C8-guanine adduct formation. Local distortion of the DNA, or the charged nitrenium ion, may be required. The complexes presented here serve as starting structures for ongoing quantum-mechanical studies of nitrenium ion stability and covalent adduct formation.
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BibTeX
@misc{selvaraj2026binding,
title = {{Binding Mode of the Heterocyclic Amine 2-Amino-9H-pyrido[2,3-b] indole (AαC) to DNA Elucidated by Molecular Docking and Molecular Dynamics Simulation}},
author = {Gurudeeban Selvaraj and Satyavani Kaliamurthi and Gilles H. Peslherbe and Dong-qing Wei},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010963/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010963/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Binding Mode of the Heterocyclic Amine 2-Amino-9H-pyrido[2,3-b] indole (AαC) to DNA Elucidated by Molecular Docking and Molecular Dynamics Simulation
AU - Gurudeeban Selvaraj
AU - Satyavani Kaliamurthi
AU - Gilles H. Peslherbe
AU - Dong-qing Wei
PY - 2026
DA - 2026/10/23
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010963/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010963/v1
AB - Background: 2-Amino-9H-pyrido[2,3-b]indole (AαC) is a mutagenic and carcinogenic heterocyclic aromatic amine formed by pyrolysis of proteins in cooked meat and present in tobacco smoke. After metabolic activation to a reactive nitrenium ion, it modifies DNA covalently, mainly at guanine. How AαC first associates with DNA, before any covalent bond forms, is not well understood. Methods: We docked AαC to three B-DNA dodecamers (PDB IDs 1BNA, 2Z2G and 2HKC) with PatchDock and FireDock, and ran explicit-solvent molecular dynamics (MD) simulations of the docked complexes in NAMD 2.13 with the CHARMM36 force field (1BNA: 10 ns; 2Z2G: 50 ns; NPT, 300 K, 0.15 M NaCl). Results: AαC bound in the minor groove of all three dodecamers, with global binding energies of -50.08 (1BNA), -53.41 (2Z2G) and -45.22 kcal/mol (2HKC). Atomic van der Waals terms contributed -16.41 to -18.36 kcal/mol, and single hydrogen bonds to thymine, guanine or adenine oxygen atoms were identified (2.2–2.8 Å). In the simulations AαC remained bound with a low, stable backbone RMSD, whereas the DNA backbone fluctuated considerably more. The minor-groove poses were poorly oriented for covalent attack when the base pairs were intact and canonical. Conclusions: Neutral AαC forms stable, groove-bound non-covalent complexes with B-DNA, but these complexes do not by themselves position the amine for C8-guanine adduct formation. Local distortion of the DNA, or the charged nitrenium ion, may be required. The complexes presented here serve as starting structures for ongoing quantum-mechanical studies of nitrenium ion stability and covalent adduct formation.
ER -