Among the different intrastrand quadruplex structures that can arise from duplex DNA, it has been discovered that the nucleotide sequences (GGA).sub.4 (SEQ ID NO: 1) and (GGA).sub.3GG (SEQ ID NO: 2) form biologically significant quadruplex structures. Thus, provided herein are methods for identifying molecules that modulate the biological activity of quadruplex DNA comprising the nucleotide sequence (GGA).sub.4 (SEQ ID NO: 1) or the nucleotide sequence (GGA).sub.3GG (SEQ ID NO: 2), and specifically, methods for identifying molecules that bind such quadruplexes. Also provided herein are methods for modulating the biological activity of a biologically significant native quadruplex DNA with a molecule identified by the methods described herein.