Sampling the potential energy surface of a DNA duplex damaged by a food carcinogen: Force field parameterization by ab initio quantum calculations and conformational searching using molecular mechanics computations.

摘要

The heterocyclic amine 2-amino-3-methylimidazo (4, 5-f) quinoline (IQ) is one of a number of carcinogens found in barbecued meat and fish. It induces tumors in mammals and is probably involved in human carcinogenesis, because of great exposure to such food carcinogens.; IQ is biochemically activated to a derivative which reacts with DNA to form a covalent adduct. This adduct may deform the DNA and consequently cause a mutation. which may initiate carcinogenesis. To understand this cancer initiating event, it is necessary to obtain atomic resolution structures of the damaged DNA. No such structures are available experimentally due to synthesis difficulties. Therefore, we employ extensive molecular mechanics and dynamics calculations for this purpose.; The major IQ-DNA adduct in the specific DNA sequence $d5\prime G1G2C\; G3CCA3\prime$–$d5\prime TGGCGCC3\prime$ with IQ modified at G₃ is studied. The $d5\prime G1G2C\; G3CC3\prime$ sequence has recently been shown to be a hot-spot for mutations when IQ modification is at G₃. Although this sequence is prone to −2 deletions via a “slippage mechanism” even when unmodified, a key question is why IQ increases the mutation frequency of the unmodified DNA by about 104 fold. Is there a structural feature imposed by IQ that is responsible?; The molecular mechanics and dynamics program AMBER for nucleic acids with the latest force field was chosen for this work. This force field has been demonstrated to reproduce well the B-DNA structure. However, some parameters, the partial charges, bond lengths and angles, dihedral parameters of the modified residue, are not available in the AMBER database. We parameterized the force field using high level ab initio quantum calculations. We created 800 starting conformations which uniformly sampled in combination at 18° intervals three torsion angles that govern the IQ-DNA orientations, and energy minimized them. The most important structures are abnormal; the IQ damaged guanine is rotated out of its standard B-DNA orientations, compromising its ability to act as a faithful template during DNA replication.