G-quadruplexes (GQs) are guanine-rich, noncanonical nucleic acid structures that play fundamental roles in genomic stability and the regulation of gene expression. GQs are enriched in promoter sequences of growth regulatory genes and proto-oncogenes like c-kit. The c-kit gene encodes for a receptor tyrosine kinase linked to gastrointestinal stromal tumors, mast cell disease, and leukemia and its promoter region contains unique GQ-forming sequences. Such promoter GQs are prevalent throughout the human genome and their destabilization or dysregulation are often implicated in disease. GQs are topologically diverse, influenced by primary and secondary structure, ion interactions, solvent concentration, and the presence of other biomolecules. Therefore, a greater understanding of GQ structure, conformational dynamics, and ion binding properties can be leveraged to develop novel, GQ-targeting therapeutics. Molecular dynamics simulations are well suited for providing these fundamental insights to build towards computer-aided drug design. GQ-cation interactions largely influence folding and previous studies suggest electronic polarization is important for modeling ion-ion and ion-DNA interactions in GQs. Thus, we used both the CHARMM36 nonpolarizable and Drude-2017 polarizable force fields to characterize the impact of different monovalent cations on c-kit1 stability and contextualize the effects of polarization. c-kit1 systems were set up in K+, Na+, and Li+ as well as mixed K+-Na+ and K+-Li+. Simulations with the Drude force fields produced more realistic models of ion-ion and stabilizing noncanonical interactions. Further, simulations showed differences in GQ stability, local ion alignment in the tetrad core, ion hydration structure, and bulk ion binding between systems with different ions. We also quantified the ionic atmosphere around the c-kit1 GQ in systems of mixed K+-Na+ and K+-Li+ by computing volume Jacobian-normalized radial distribution functions. Such descriptions of GQ-ion dynamics help rationalize the preference for K+ by DNA GQs and provide insight into noncanonical nucleic acids for which little experimental data exist.

Influence of monovalent cations on the dynamics of the c-kit1 promoter G-quadruplex using polarizable molecular dynamics simulations

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.