UCLA

The relative genotoxicity of different polycyclic aromatic hydrocarbons (PAHs) is widely thoughtto be a function of the structural and thermodynamic features of their corresponding PAH-DNA adducts. As a result, accurate parameters for molecular mechanics force fields are crucial to the study of such systems via molecular dynamics (MD). While transferability of parameters among structurally similar molecular systems is frequently a goal when parameterizing novel residues for the CHARMM force field, we will show that planar bay region and non-planar fjord region PAH- DNA adduct systems require distinct dihedral terms to accurately model the torsional potential energy surface of the adduct covalent bond that links a PAH-diol-epoxide and adenine, despite identical atomic connectivity. We then examine the use of the Truncated Singular Value Decom- position and Tikhonov Regularization in standard form to address ill-posed least squares problems Ax = b that frequently arise in molecular mechanics force field parameter optimization. Utilizing the Discrete Picard Condition and/or a well-defined gap in the singular value spectrum when A has a well-determined numerical rank, we are able to systematically determine truncation and in turn regularization parameters that are correspondingly used to produce truncated and regularized solutions to the ill-posed least squares problem at hand. These solutions in turn result in optimized force field dihedral terms that accurately parameterize the torsional energy landscape. As the solu- tions produced by this approach are unique, it has the advantage of avoiding the multiple iterations and guess and check work often required to optimize molecular mechanics force field parameters. With optimized parameters for bay and fjord region PAH-DNA adduct systems developed, we con- duct alchemical free energy perturbation calculations over closed thermodynamic cycles in order to gauge the relative genotoxicities of several IARC Group 2A/B and 3 PAHs in the NRAS(Q61) DNA sequence context. These calculations reveal that the fjord region PAHs examined in this work as well as other IARC Group 2A/B and 3 PAHs exhibit greater relative binding affinity as compared to the IARC Group 1 known human carcinogen B[a]P. These PAHs are also less likely to form productive PAH-DNA protein binding complexes required in the recognition step of global genomic - nucleotide excision repair, indicating that they are more likely to persist and induce mutations in subsequent DNA replication cycles. Further examination reveals that the intercalated conformation and structural differences among PAH-DNA adducts have an impact on stabilizing van der Waals interactions and hydrogen bonding between nucleobase pairs in NRAS(Q61) that are generally associated with trends in relative binding free energies.