Polarizable Force Field for DNA Based on the Classical Drude Oscillator: II. Microsecond Molecular Dynamics Simulations of Duplex DNA

Abstract

The structure and dynamics of DNA are governed by a sensitive balance between base stacking and pairing, hydration, and interactions with ions. Force field models that include explicit representations of electronic polarization are capable of more accurately modeling the subtle details of these interactions versus commonly used additive force fields. In this work, we validate our recently refined polarizable force field for DNA based on the classical Drude oscillator model, in which electronic degrees of freedom are represented as negatively charged particles attached to their parent atoms via harmonic springs. The previous version of the force field, called Drude-2013, produced stable A- and B-DNA trajectories on the order of hundreds of nanoseconds, but deficiencies were identified that included weak base stacking ultimately leading to distortion of B-DNA duplexes and unstable Z-DNA. As a result of extensive refinement of base nonbonded terms and bonded parameters in the deoxyribofuranose sugar and phosphodiester backbone, we demonstrate that the new version of the Drude DNA force field is capable of simulating A- and B-forms of DNA on the microsecond time scale and the resulting conformational ensembles agree well with a broad set of experimental properties, including solution X-ray scattering profiles. In addition, simulations of Z-form duplex DNA in its crystal environment are stable on the order of 100 ns. The revised force field is to be called Drude-2017.

Polarizable force field for RNA based on the classical drude oscillator

“…Corresponding molecular mechanical (MM) calculations were performed using the Drude‐2017 force field in the CHARMM program . All MM calculations were performed analogously to the corresponding QM calculations; that is, any fixed degrees of freedom during QM optimizations were similarly restrained in CHARMM to ensure a direct comparison between the results.…”

“…All of the atom types used to describe uracil in the Drude force field are shared by cytosine and thymine, which were refined in our previous work on DNA . The electrostatic parameters derived by Baker et al for uracil were applied in conjunction with the refined LJ parameters of the Drude‐2017 atom types and evaluated in CHARMM by enforcing the intermolecular restraints described above via the LONEPAIR facility.…”

“…Bonded and nonbonded parameters for R3PS were initially taken from the Drude‐2017 DNA force field, and the 2′‐hydroxyl group was assigned the nonbonded parameters of the Drude model of 2‐propanol developed as part of the primary and secondary alcohol series . The initial configuration of R3PS was generated using the CHARMM program …”

“…The present work extends the existing Drude‐2017 DNA force field to include RNA to create a comprehensive Drude polarizable force field for nucleic acids. Specific emphasis is placed on proper sampling of the 2′‐hydroxyl group of the ribose sugar, base stacking interactions, and interactions of the 2′‐hydroxyl group with water.…”

Molecular dynamics simulations using the drude polarizable force field on GPUs with OpenMM: Implementation, validation, and benchmarks

“…We evaluated protein (ubiquitin, PDB 1UBQ) 35 , DNA (Dickerson-Drew dodecamer, EcoRI, PDB 1BNA), 36 and 1 M MgCl 2 systems, all taken from previous studies. 25,37,38 Each system was solvated in SWM4-NDP water 39 and the EcoRI system included ~100 mM NaCl. The differences between forces computed by the two programs were evaluated for each atom in the systems using the relative errors defined by the L2 norm between its (x,y,z) component: $$e=\sqrt{{\sum }_{i=x,y,z}{\left(\frac{F_i^{\text{OpenMM}}-F_i^{\text{CHARMM}}}{F_i^{\text{CHARMM}}}\right)}^2}$$…”