Atomic level rendering of DNA-drug encounter.
Computer simulations have been demonstrated to be important for unraveling atomic mechanisms in biological systems. In this study, we show how combining unbiased molecular dynamic simulations with appropriate analysis tools can successfully describe metal-based drug interactions with DNA. To elucidate the noncovalent affinity of cisplatin's family to DNA, we performed extensive all-atom molecular dynamics simulations (3.7 μs total simulation length). The results show that the parent drug, cisplatin, has less affinity to form noncovalent adducts in the major groove than its aquo complexes. Furthermore, the relative position in which the drugs enter the major groove is dependent on the compound's net charge. Based on the simulations, we estimated noncovalent binding free energies through the use of Markov state models. In addition, and to overcome the lack of experimental information, we employed two additional methods: Molecular Mechanics Poisson-Boltzmann Surface Area (MMPB-SA) and steered molecular dynamics with the Jarzynski estimator, with an overall good agreement between the three methods. All complexes show interaction energies below 3 kcal/mol with DNA but the charged hydrolysis products have slightly more favorable binding free energies than the parent drug. Moreover, this study sets the precedent for future unbiased DNA-ligand simulations of more complex binders.
Joint BSC-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
Maria F
MF
Lucas
Joint BSC-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
Israel
I
Cabeza de Vaca
Joint BSC-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain.
Ryoji
R
Takahashi
Department of Physical Chemistry, University of Barcelona (UB), Barcelona, Spain, and Institut de Recerca en Química Teòrica i Computacional (IQTCUB), Barcelona, Spain.
Jaime
J
Rubio-Martínez
Joint BSC-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, E-08010 Barcelona, Spain. Electronic address: victor.guallar@bsc.es.
Víctor
V
Guallar
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D013816:Thermodynamics
D000970:Antineoplastic Agents; D004247:DNA; D002945:Cisplatin