Effects of Formaldehyde on DNA
A Molecular Dynamics Study of Formaldehyde Adducts
Formaldehyde is a known carcinogen, which damages and mutates DNA in the cells of mammals. Acute and chronic exposure to formaldehyde may occur in both occupational settings (e.g., embalmers) and from several household products (e.g., insulation, particle boards, and carpeting). Upon human exposure to formaldehyde, several DNA adducts may be formed, including those with the amino groups of guanine (denoted CH2OH-N2-G), cytosine (CH2OH-N4-C), and adenine (CH2OH-N6-A). Each of these adducts consists of a methoxy moiety linked to the exocyclic amino group of the respective DNA nucleobase. The methoxy moiety can interfere with several noncovalent interactions within a DNA helix, including Watson-Crick hydrogen bonding, Hoogsteen hydrogen bonding, and stacking interactions between neighboring DNA nucleobases. These interactions are essential to the normal function of DNA and their disruption could lead to mutations when DNA is copied, which in turn lead to health effects such as cancer. Although insight into the implications on formaldehyde adducts are currently lacking from experimental studies, computational chemistry can be used to predict the effects of the methoxy moiety on the nucleobase interactions and the mutagenicity of these adducts. In the current study, molecular dynamics (MD) simulations, along with advanced structural analysis and energy calculations, were used to study the preferred conformations of the nucleobase within damaged DNA, and thereby characterize the structural impacts of this damage. Using this analysis, key insight was gained into the mutagenicity of the CH2OH adducts and the data obtained can be used to direct future biochemical studies of the harmful effects of these lesions.