Aromatic base stacking in DNA: From ab initio calculations to molecular dynamics simulations

Aromatic stacking of nucleic acid bases is one of the key players in determ ining the structure and dynamics of nucleic acids. The arrangement of nucle ic acid bases with extensive overlap of their aromatic rings gave rise to n umerous often contradictory suggestions about the physical origins of stack ing and the possible role of delocalized electrons in stacked aromatic pi. systems, leading to some confusion about the issue. The recent advance of c omputer hardware and software finally allowed the application of state of t he art quantum-mechanical approaches with inclusion of electron correlation effects to study aromatic base stacking, now providing an ultimitate quali tative description of the phenomenon. Base stacking is determined by an int erplay of the three most commonly encountered molecular interactions: dispe rsion attraction, electrostatic interaction, and short-range repulsion. Unu sual (aromatic-stacking specific) energy contributions were in fact not evi denced and are not necessary to describe stacking. The currently used simpl e empirical potential form, relying on atom-centered constant point charges and Lennard-Jones van der Waals; terms, is entirely able to reproduce the essential features of base stacking. Thus, we can conclude that base stacki ng is in principle one of the best described interactions in current molecu lar modeling and it allows to study base stacking in DNA using large-scale classical molecular dynamics simulations. Neglect of cooperativity of stack ing appears to be the most serious approximation of the currently used forc e field form. This review summarizes recent developments in the field. It is written for an audience that is not necessarily expert in computational quantum chemist ry and follows up on our previous contribution (Sponer et. al., J. Biomol. Struct. Dyn. 14, 117, (1996)). First, the applied methodology, its accuracy , and the physical nature of base stacking is briefly overviewed, including a comment on the accuracy of other molecular orbital methods and force fie lds. Then, base stacking is contrasted with hydrogen bonding, the other dom inant force in nucleic acid structure. The sequence dependence and cooperat ivity of base stacking is commented on, and finally a brief introduction in to recent progress in large-scale molecular dynamics simulations of nucleic acids is provided. Using four stranded DNA assemblies as an example, we de monstrate the efficacy of current molecular dynamics techniques that utiliz e refined and verified force fields in the study of stacking in nucleic aci d molecules.