Ion Binding Properties and Dynamics of the 2 G-Quadruplex Using a Polarizable Force Field.

G-quadruplexes (GQs) are topologically diverse, highly thermostable noncanonical nucleic acid structures that form in guanine-rich sequences in DNA and RNA. GQs are implicated in transcriptional and translational regulation and genome maintenance, and deleterious alterations to their structures contribute to diseases such as cancer. The expression of the B-cell lymphoma 2 (Bcl-2) antiapoptotic protein, for example, is under transcriptional control of a GQ in the promoter of the 2 gene. Modulation of the 2 GQ by small molecules is of interest for chemotherapeutic development but doing so requires knowledge of the factors driving GQ folding and stabilization. To develop a greater understanding of the electrostatic properties of the 2 promoter GQ, we performed molecular dynamics simulations using the Drude-2017 polarizable force field and compared relevant outcomes to the nonpolarizable CHARMM36 force field. Our simulation outcomes highlight the importance of dipole-dipole interactions in the 2 GQ, particularly during the recruitment of a bulk K ion to the solvent-exposed face of the tetrad stem. We also predict and characterize an "electronegative pocket" at the tetrad-long loop junction that induces local backbone conformational change and may induce local conformational changes at cellular concentrations of K. These outcomes suggest that moieties within the 2 GQ can be targeted by small molecules to modulate -2 GQ stability.