Molecular dynamics simulations of ssDNA and gmp/G-quadruplex

Abstract

Even as more information becomes available using experimental methods, chemistry is evolving into a discipline in which both theoretical and experimental aspects can be used to better understand and interpret chemical processes and mechanisms. Molecular dynamics simulations provide a means by which we may explore atomic interactions within molecules in a straightforward and cost-effective manner. Here we use molecular dynamics to study two separate but related areas of research in the McGown group: self-assembly of guanosine monophosphate (GMP) into G-quadruplex (G4) structures, and the mechanism of separation of same-length, single-stranded DNA based on sequence in capillary zone electrophoresis.

In the second project, eight variations of a ssDNA strand were simulated in water and buffer systems over 50 ns, mirroring experimental parameters used in capillary electrophoresis separation of the strands. These strands are variations of an oligonucleotide of polyT that is 15 nucleotides in length. The variants contained only single or double mutations in order to see the effect of each type of base on the system. The most notable result found in these simulations is the differences in the conformations of the different strands by the end of simulation. Those strands which contain C and T bases in the mutated position collapse to a stable state, while those containing A and G remain relatively elongated. The difference in structure was explored by examining: the change in structure over time from an elongated state, the compact nature of the strands, and the solvation by water, buffer, and K+ over the entire strand and at the mutation site. Finally, a collapsed structure was taken and the central base mutated to G. This mutation allowed the structure to return to a semi-elongated state, further showing the significant impact of an individual base on the configuration of ssDNA. These studies imply that the basis of the separation of the strands by capillary zone electrophoresis is differences in their conformations.

The simulation of a single GMP in vacuum and water systems provides insight into the impact of water on GMP self-assembly, keeping a single GMP molecule from hydrogen bonding to itself. The planarity of the molecule is noted, as this is a necessary component of the larger guanosine complexes, and this is mainly due to the base.This structure is used to build larger G4 structures, many of which are ultimately unstable. Hydrogen bonding between GMP molecules along with small numbers of central K+ ions does not seem sufficient to keep planar G4 structures together. However, larger helices retain much of their original shape, including planar, stacked bases and a vertical K+ core. These results significantly impact our work on guanosine based gels and our understanding of GMP complex structures.