We present a new all-atom Monte Carlo technique capable of performing quick and accurate DNA–ligand conformational sampling. In particular, and using the PELE software as a frame, we have introduced an additional force field, an implicit solvent, and an anisotropic network model to effectively map the DNA energy landscape. With these additions, we successfully generated DNA conformations for a test set composed of six DNA fragments of A-DNA and B-DNA. Moreover, trajectories generated for cisplatin and its hydrolysis products identified the best interacting compound and binding site, producing analogous results to microsecond molecular dynamics simulations. Furthermore, a combination of the Monte Carlo trajectories with Markov State Models produced noncovalent binding free energies in good agreement with the published molecular dynamics results, at a significantly lower computational cost. Overall our approach will allow a quick but accurate sampling of DNA–ligand interactions.

The authors thank the Barcelona Supercomputing Center for computational resources. This work was supported by grants from the European Research Council—2009-Adg25027-PELE European project and the Spanish Ministry of Economy and Competitiveness CTQ2013-48287 and “Juan de la Cierva” to F.L.

Peer Reviewed