TY - JOUR
T1 - Early stage intercalation of doxorubicin to DNA fragments observed in molecular dynamics binding simulations
AU - Lei, Hongxing
AU - Wang, Xiaofeng
AU - Wu, Chun
N1 - Funding Information:
This project was funded by the National Science Foundation of China to HL (Grant 30870474 ). Usage of AMBER and VMD graphics packages is gratefully acknowledged.
PY - 2012/9
Y1 - 2012/9
N2 - The intercalation mode between doxorubicin (an anticancer drug) and two 6-base-pair DNA model fragments (d(CGATCG)2 and d(CGTACG) 2) has been well studied by X-ray crystallography and NMR experimental methods. Yet, the detailed intercalation pathway at molecular level remains elusive. In this study, we conducted molecular dynamics binding simulations of these two systems using AMBER DNA (parmbsc0) and drug (GAFF) force fields starting from the unbound state. We observed outside binding (minor groove binding or end-binding) in all six independent binding simulations (three for each DNA fragment), followed by the complete intercalation of a drug molecule in two simulations (one for each DNA fragment). First, our data directly supported that the minor groove binding is the dominant pre-intercalation step. Second, we observed that the opening and flipping of a local base pair (A3-T10 for d(CGATCG)2 and C1-G12 for d(CGTACG) 2) in the two intercalation trajectories. This locally cooperative flipping-intercalation mechanism was different from the previously proposed rise-insertion mechanism by which the distance between two neighboring intact base pairs increases to create a space for the drug insertion. Third, our simulations provided the first set of data to support the applicability of the AMBER DNA and drug force fields in drug-DNA atomistic binding simulations. Implications on the kinetics pathway and drug action are also discussed.
AB - The intercalation mode between doxorubicin (an anticancer drug) and two 6-base-pair DNA model fragments (d(CGATCG)2 and d(CGTACG) 2) has been well studied by X-ray crystallography and NMR experimental methods. Yet, the detailed intercalation pathway at molecular level remains elusive. In this study, we conducted molecular dynamics binding simulations of these two systems using AMBER DNA (parmbsc0) and drug (GAFF) force fields starting from the unbound state. We observed outside binding (minor groove binding or end-binding) in all six independent binding simulations (three for each DNA fragment), followed by the complete intercalation of a drug molecule in two simulations (one for each DNA fragment). First, our data directly supported that the minor groove binding is the dominant pre-intercalation step. Second, we observed that the opening and flipping of a local base pair (A3-T10 for d(CGATCG)2 and C1-G12 for d(CGTACG) 2) in the two intercalation trajectories. This locally cooperative flipping-intercalation mechanism was different from the previously proposed rise-insertion mechanism by which the distance between two neighboring intact base pairs increases to create a space for the drug insertion. Third, our simulations provided the first set of data to support the applicability of the AMBER DNA and drug force fields in drug-DNA atomistic binding simulations. Implications on the kinetics pathway and drug action are also discussed.
UR - https://www.scopus.com/pages/publications/84867427868
UR - https://www.scopus.com/pages/publications/84867427868#tab=citedBy
U2 - 10.1016/j.jmgm.2012.05.006
DO - 10.1016/j.jmgm.2012.05.006
M3 - Article
C2 - 23079648
AN - SCOPUS:84867427868
SN - 1093-3263
VL - 38
SP - 279
EP - 289
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
ER -