Because of high stability and slow unfolding rates of G-quadruplexes (G4), cells 
have evolved specialized helicases that disrupt these non-canonical DNA and RNA 
structures in an ATP-dependent manner. One example is DHX36, a DEAH-box 
helicase, which participates in gene expression and replication by recognizing 
and unwinding parallel G4s. Here, we studied the molecular basis for the high 
affinity and specificity of DHX36 for parallel-type G4s using all-atom molecular 
dynamics simulations. By computing binding free energies, we found that the two 
main G4-interacting subdomains of DHX36, DSM and OB, separately exhibit high G4 
affinity but they act cooperatively to recognize two distinctive features of 
parallel G4s: the exposed planar face of a guanine tetrad and the unique 
backbone conformation of a continuous guanine tract, respectively. Our results 
also show that DSM-mediated interactions are the main contributor to the binding 
free energy and rely on making extensive van der Waals contacts between the 
GXXXG motifs and hydrophobic residues of DSM and a flat guanine plane. 
Accordingly, the sterically more accessible 5'-G-tetrad allows for more 
favorable van der Waals and hydrophobic interactions which leads to the 
preferential binding of DSM to the 5'-side. In contrast to DSM, OB binds to G4 
mostly through polar interactions by flexibly adapting to the 5'-terminal 
guanine tract to form a number of strong hydrogen bonds with the backbone 
phosphate groups. We also identified a third DHX36/G4 interaction site formed by 
the flexible loop missing in the crystal structure.