Articles

Journal of the American Society for Mass Spectrometry

, Volume 18, Issue 10, pp 1760-1773

First online:

Gas-phase stability of G-quadruplex DNA determined by electrospray ionization tandem mass spectrometry and molecular dynamics simulations

  • Carolyn L. MazzitelliAffiliated withDepartment of Chemistry and Biochemistry, University of Texas at Austin
  • , Junmei WangAffiliated withEncysive Pharmaceuticals Inc.
  • , Suncerae I. SmithAffiliated withDepartment of Chemistry and Biochemistry, University of Texas at Austin
  • , Jennifer S. BrodbeltAffiliated withDepartment of Chemistry and Biochemistry, University of Texas at Austin Email author 

Abstract

The relative gas-phase stabilities of seven quadruplex DNA structures, [d(TG4T)]4, [d(T2G3T)]4, [d(G4T4G4)]2, [d(T2AG3)2]2, d(T2AG3)4, d(T2G4)4, and d(G2T4)4, were investigated using molecular dynamics simulations and electrospray ionization mass spectrometry (ESI-MS). MD simulations revealed that the G-quadruplexes maintained their structures in the gas phase although the G-quartets were distorted to some degree and ammonium ions, retained by [d(TG4T)]4 and [d(T2G3T)]4, played a key role in stabilizing the tetrad structure. Energy-variable collisional activated dissociation was used to assess the relative stabilities of each quadruplex based on E1/2 values, and the resulting order of relative stabilities was found to be [d(TG4T)]4≫d(T2AG3)4∼d(T2G4)4 > [d(T2G3T)]4>[d(T2AG3)2]2∼d(G2T4)4∼[d(G4T4G4)]2. The stabilities from the E1/2 values generally paralleled the RMSD and relative free energies of the quadruplexes based on the MD energy analysis. One exception to the general agreement is [d(G4T4G4)]2, which had the lowest E1/2 value, but was determined to be the most stable quadruplex according to the free-energy analysis and ranked fourth based on the RMSD comparison. This discrepancy is attributed to differences in the fragmentation pathway of the quadruplex.