Ab Initio Study of the Structure and Stability of DNA Base Pairs in the Presence of Bound Waters and Metal Cations

INTRODUCTION Nucleic acids were first isolated in 1869 by Friedrich Miescher, but it took almost 75 years to demonstrate that DNA was the carrier of genetic information. One of the most important steps in the study of DNA was made in 1953 by James Watson and Francis Crick, who proposed the three-dimensional right-handed double-helical B- DNA model. The Watson-Crick structure of DNA was of such importance because also suggested the molecular mechanism of heredity. Nucleic acids are linear polymers of nucleotides whose phosphates bridge the 3’ and 5’ positions of successive sugar residues. The B-DNA consists of two polynucleotide strands that wind about a common axis with a right handed twist to form a double helix. The bases occupy the core of the helix and sugar-phosphate chains are coiled about its periphery. Each base is hydrogen bonded to a base on the opposite strand to form an almost planar base pair. In particular, the B-DNA structure can accommodate without strain only two types of base pairs: adenine- thymine and cytosine-guanine (in the Watson-Crick arrangement). The specific hydrogen bonding association of bases, a phenomenon known as complementary base pairing, is not only fundamental to important biological processes such as replication and transcription, but also a major determinant of nucleic acid structure. More advanced experimental studies revealed that DNA can also adopt other double helical forms, such as A and Z-DNA, and many other three-dimensional forms, including triple and quadruple helices, in which the base pairing does not always adopt the Watson-Crick scheme. It is important to understand that nucleic acids function through their interaction with other molecules. The presence of water and ions can profoundly influence the conformation, and therefore the properties of DNA. Indeed, as Privé et al. 1 note: “…DNA is built from five structural elements rather than three: the familiar bases, sugars, and phosphates, but also ordered waters and bound counterions.” 1