Computation of dispersion and other intermolecular interactions and their relationship to carcinogen-induced DNA damage

Christos Deligkaris, Purdue University

Abstract

Noncovalent interactions, such as the attractive component of van der Waal forces known as dispersion, play an important role in determining the structure of macrobiomolecules. Proper inclusion of noncovalent effects in computational simulations may be crucial for elucidating biochemical function. However, most practical implementations of Kohn-Sham density functional theory, a microscopic theory of electronic structure theory, do not completely or accurately capture dispersion interactions. We have implemented a computationally inexpensive yet accurate methodology for inclusion of dispersion in interaction energies via, otherwise accurate, density functional calculations. Carcinogens, molecules that promote cancer, cause changes in the genetic information contained in DNA due to associated mutations. Carcinogens can create DNA adducts and, during DNA repair or replication, mutations may be introduced. To study the effect of some carcinogens on DNA, we separate the complementary roles of physical (i.e., noncovalent) and chemical intermolecular interactions. Herein, we mainly focus on the former. These physical forces bring carcinogens in positions (noncovalent binding sites) where they can eventually chemically bind to DNA. By minimizing a relevant free energy function we found the most stable (i.e., lowest-energy) noncovalent binding sites of two tobacco smoke carcinogens, BPDE and acrolein, in exon 1 of a human proto-oncogene, namely the K-ras gene. The methylation of the cytosine base, naturally found in DNA, can enhance the binding of a tobacco smoke carcinogen (BPDE) and a chemotherapeutic agent (mitomycin) to DNA. In addition, tobacco smoke carcinogen-induced DNA damage is associated with mutations at hot spots of a human tumor suppressor gene (TP53) in smoking-induced lung cancer. Thus, cytosine methylation contributes to mutations of the tumor suppressor gene TP53 which promotes development of cancerous cells. The TP53 gene encodes the protein p53 which is crucial for the functionality of cells and has been named “the guardian of the genome''. By performing electronic structure calculations at the molecular level on TP53, we have found some effects of cytosine methylation on DNA's geometric and electronic structure and discuss their implications on DNA damage.

Degree

Ph.D.

Advisors

Rodriguez, Purdue University.

Subject Area

Molecular biology|Genetics|Oncology

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