Characterizing the Impact of Cancer Mutations in DNA Base Editing Enzymes

Abstract

We have developed a comprehensive approach to find and characterize the impact of cancer mutants on any protein, and have applied it to DNA modification enzymes. This approach is an extension of conventional genome wide-association studies (GWAS). Our approach employs a new method for discovery and statistical validation of single nucleotide polymorphisms (SNPs) on specific genes called HyDn-SNP-S, followed by atomistic simulations via molecular dynamics (MD) and/or quantum mechanics/molecular mechanics (QM/MM) techniques. We will present the details of our mutant discovery and characterization approach, as well as examples of cancer mutations on three different DNA modification enzymes. These examples include a breast cancer mutation on DNA polymerase l, a prostate cancer mutation on the DNA dealkylase ALKBH7, and a lung cancer mutation on the cytidine deaminaseAPOBEC3H. Our simulations provide atomistic details about how these mutations affect the specific protein structure and/or function, which have been further validated by experimental methods.