Ion Binding to the bcl-2 G-Quadruplex from Polarizable Simulations with the Drude Force Field

Abstract

G-quadruplexes (GQs) are noncanonical nucleic acid structures that can form in guanine-rich sequences and can adopt many diverse conformations depending on their constituent nucleotides. GQs are commonly present in DNA promoter regions, so alterations to their structures can contribute to diseases such as cancer. The B-cell lymphoma 2 (bcl-2) proto-oncogene codes for a protein that inhibits cell apoptosis and overexpression of bcl-2 is associated with cancer progression. Transcription of bcl-2 is controlled by two promoters, one of which contains a GQ-forming sequence. Understanding the stabilizing forces in this structure may lead to novel chemotherapeutic design. There are gaps in our current understanding of under what conditions GQs fold, which is crucial information that can give insight into the equilibrium of GQ conformations. To advance our understanding of the dominant bcl-2 promoter GQ, we performed molecular dynamics (MD) simulations using the Drude-2017 polarizable force field. Our simulation outcomes highlight two distinct changes within the GQ that coincide with ion binding. The first is the recruitment of a bulk K+ ion to the solvent-exposed face of the tetrad stem, which led to changes in base dipole moments and the K+ interaction energies of the guanines within the tetrad core. The second is the emergence of an “electronegative pocket” between the tetrad core and the long loop below the tetrad core. Ion binding in the electronegative pocket induces a backbone conformational change that may be relevant for inducing local conformational changes at K+ concentrations similar to those found in the cell. These results suggest two different locations within the bcl-2 GQ that may be targeted by small molecules to induce conformational changes.