We explore the process of base-flipping for four central bases, adenine, guanine, cytosine, and thymine, in a deoxyribonucleic acid (DNA) duplex using the energy landscape perspective. NMR imino-proton exchange and fluorescence correlation spectroscopy studies have been used in previous experiments to obtain lifetimes for bases in paired and extrahelical states. However, the difference of almost 4 orders of magnitude in the base-flipping rates obtained by the two methods implies that they are exploring different pathways and possibly different open states. Our results support the previous suggestion that minor groove opening may be favored by distortions in the DNA backbone and reveal links between sequence effects and the direction of opening, i.e., whether the base flips toward the major or the minor groove side. In particular, base flipping along the minor groove pathway was found to align toward the 5' side of the backbone. We find that bases align toward the 3' side of the backbone when flipping along the major groove pathway. However, in some cases for cytosine and thymine, the base flipping along the major groove pathway also aligns toward the 5' side. The sequence effect may be caused by the polar interactions between the flipping-base and its neighboring bases on either of the strands. For guanine flipping toward the minor groove side, we find that the equilibrium constant for opening is large compared to flipping via the major groove. We find that the estimated rates of base opening, and hence the lifetimes of the closed state, obtained for thymine flipping through small and large angles along the major groove differ by 6 orders of magnitude, whereas for thymine flipping through small angles along the minor groove and large angles along the major groove, the rates differ by 3 orders of magnitude.