Recently, a research team led by Prof. LEI Hongxing at Beijing Institute of Genomics (BIG), Chinese Academy of Sciences (CAS), analyzed the intercalation pathway of doxorubicin (an anticancer drug) to DNA fragments by performing molecular dynamics binding simulations, and proposed a new flipping-intercalation mechanism by which the insertion of the drug is directly coupled with a local base flipping after an outside binding. Doxorubicin is a widely used anticancer drug, which can effectively treat acute leukemia, stomach cancer, liver cancer and other malignant tumors. The anti-cancer activity of this drug is likely due to their intercalation into DNA fragments, which may disrupt replication and transcription of genomic DNA and lead to the death of cancer cells. Yet, the detailed intercalation pathway at molecular level remains elusive. Starting from an unbound state (a B-DNA fragment + two free doxorubicin molecules), Prof. LEI and his research team preformed all-atom molecular dynamics (MD) binding simulations with explicit water. The simulations allowed us to validate the force fields and to probe the structural and energetic nature of the dynamic binding process with high spatial and temporal resolution. From the simulation trajectories, the researchers observed multiple binding modes including end-stacking, minor groove binding and intercalation modes. The minor groove-bound state is the “outside bound” intermediate state towards the final intercalation, in other words, is the dominant pre-intercalation step. According to the results of in-depth analyses, Prof. LEI proposed a new flipping-intercalation mechanism by which the insertion of the drug is directly coupled with a local base flipping after an outside binding. This observed flipping-intercalation mechanism is completely different from the previously proposed rise-insertion mechanism which requires a global rise between the two base pairs to create a space for the insertion of the drug in the absence of any base pair flipping. Prof. LEI indicated that “The discovery of the flipping-intercalation mechanism will provide a hint for the developing new anticancer drugs which has high efficiency and low toxicity. For one hand, the sugar part of the designed drug molecule can selectively induce the flipping of DNA base. For another hand, the ring part of the designed drug can insert between adjacent base pairs efficiently.” Representative structures in the intercalation trajectory of sequence d(CGATCG)2 .(Image by LEI's group) Paper link: http://www.sciencedirect.com/science/article/pii/S1093326312000678?v=s5 Contact: Prof. LEI Hongxing Email: leihx@big.ac.cn 
