Deoxyribonucleic acid (DNA) is an important biomolecule that serves as a storage center for genetic information. Maintaining the integrity of such a molecule is crucial for the correct expression of proteins in the body. Unsurprisingly, the regulation of DNA synthesis and repair has evolved to ensure that few errors are incorporated in the molecule. The replication of DNA is performed by a protein called DNA polymerase. An impressive feature of this protein is its high fidelity—ability to replicate DNA with few errors—and the speed at which it can replicate a strand of DNA. Although DNA polymerase has the ability to repair a misincorporated nucleotide, mistakes in DNA replication are bound to occur. The mechanisms that govern DNA synthesis, repair, and recognition have become more relevant because of recent studies of cancer etiology that show that replication errors are an important driving factor for cancer-causing mutations. Thus, understanding the behavior of mismatched base pairs in the active site can be a starting point for understanding cancer etiology at a molecular level. Traditional biophysical techniques provide a foundation for understanding protein mechanics such as recognition of mismatches. Protein structures and kinetic data from traditional techniques can be enhanced with molecular dynamic simulations, which utilize classical mechanics to model the behavior of molecules at small time steps. In more detail, molecular dynamic simulations of DNA polymerase with incorrect incoming nucleotides in the active site were conducted to understand the stability of mismatched bases in the active site and be used to identify alternative geometries. Furthermore, these simulations seek to understand preferences for certain mismatched base pairs to be edited by the polymerase.

Molecular dynamic simulations of mismatched base pairs in a B family DNA Polymerase

ACS Fall 2020 Virtual Meeting

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