Molecular flexibility in ab initio drug docking to DNA: binding-site and binding-mode transitions in all-atom Monte Carlo simulations

Abstract

The dynamics of biological processes depend on the structure and flexibility of the interacting molecules. In particular, the conformational diversity of DNA allows for large deformations upon binding. Drug–DNA interactions are of high pharmaceutical interest since the mode of action of anticancer, antiviral, antibacterial and other drugs is directly associated with their binding to DNA. A reliable prediction of drug–DNA binding at the atomic level by molecular docking methods provides the basis for the design of new drug compounds. Here, we propose a novel Monte Carlo (MC) algorithm for drug–DNA docking that accounts for the molecular flexibility of both constituents and samples the docking geometry without any prior binding-site selection. The binding of the antimalarial drug methylene blue at the DNA minor groove with a preference of binding to AT-rich over GC-rich base sequences is obtained in MC simulations in accordance with experimental data. In addition, the transition between two drug–DNA-binding modes, intercalation and minor-groove binding, has been achieved in dependence on the DNA base sequence. The reliable ab initio prediction of drug–DNA binding achieved by our new MC docking algorithm is an important step towards a realistic description of the structure and dynamics of molecular recognition in biological systems.

Computational Identification of Inhibitors of Protein-Protein Interactions

“…These include fast Fourier transform surface matching algorithms [180,181] (MolFit, MULTIDOCK, DOT, GRAMM, ZDOCK), geometric hashing [182,183] (PPD, PatchDock, BUDDA), genetic algorithms [86,98,99,103,[184][185][186][187][188][189][190][191][192] (GAsDock [99], GAPDOCK [98]), Monte Carlo sampling [93,95,[193][194][195][196] (ECEPP/3 [95], ICM-DISCO, MCDOCK [194]), and molecular or Brownian-type mechanics procedures (SmoothDock, TSCF). Recently, the impact of the inclusion of receptor flexibility in several docking methods has been presented [121].…”

“…In the Monte Carlo (MC) methods [93,95,[193][194][195][196], ligand positions near the active site are randomly generated and subsequently optimized, with the selection of steps (i.e. conformational changes) performed via the Metropolis criteria.…”

Molecular Docking: Approaches, Types, Applications and Basic Challenges

“…Molecular docking is an attractive scaffold to understand drugbiomolecular interactions for the rational drug design and discovery, as well as in the mechanistic study by placing a molecule (ligand) into the preferred binding site of the target specific region of the DNA/protein (receptor) mainly in a non-covalent fashion to form a stable complex of potential efficacy and more specificity [1,2]. The information obtained from the docking technique can be used to suggest the binding energy, free energy and stability of complexes.…”

Report of Interaction Between Calf Thymus DNA and Pyrimidine-Annulated Spiro-Dihydrofuran

“…The dominant binding class of small molecules with DNA can be classified as (i) covalent binding and (ii) non-covalent binding, including intercalative binding [2], nonspecific electrostatic interaction [3] and DNA major/minor groove binding [2]. Noncovalent binding is the predominant DNA-binding mode of the major two classes of small ligands [4][5][6][7].…”