G-quadruplexes (GQs) are noncanonical nucleic acid structures that are enriched in regulatory sequences of DNA and RNA, particularly promoters, origins of replication, and telomeres in DNA and in the 5’-untranslated regions of mRNA and in regulatory sequences in RNA viral genomes. GQ structures are characterized by stacked tetrads of Hoogsteen hydrogen-bonded guanine bases that coordinate monovalent cations, typically K+. Despite this common core, GQ structures are diverse, making them attractive targets for small-molecule drug design against a broad array of conditions. To design molecules with high affinity requires detailed knowledge of GQ structure, dynamics, and interactions with ions. A key question in GQ structure is what drives the preference for K+ ions, and if there are intrinsic electrostatic factors at play. Here, we performed unbiased and metadynamics simulations of several GQs using the Drude polarizable force field, which has been shown to more accurately model GQs than nonpolarizable force fields. We found strongly organized electric fields that originate from guanine bases in the tetrad core. The alignment of the electric field vectors and the strength of the fields at sites of K+ coordination suggest a mechanism by which GQs intrinsically prefer K+. Electric fields calculated from simulations of the c-kit1 DNA GQ with Li+ and Na+ ions bound lose their coordination and reflect distortion of the GQ structures and therefore the misalignment of electric field vectors. Binding path analysis from well-tempered metadynamics simulations shows the free energy of ion binding as a function of positions outside of the tetrad faces, with binding sites coinciding with locations of the strongest electric fields, except in instances of steric occlusion by base pairing. Thus, our results demonstrate that the interplay of cations and GQ architecture result in complementarity between K+ and the GQs, helping to rationalize selection for this cation.

Electric field effects in DNA G-quadruplexes drive ion binding

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