Derivation of Reliable Geometries in QM Calculations of DNA Structures: Explicit Solvent QM/MM and Restrained Implicit Solvent QM Optimizations of G‑Quadruplexes

Modern
dispersion-corrected DFT methods have made it possible to
perform reliable QM studies on complete nucleic acid (NA) building
blocks having hundreds of atoms. Such calculations, although still
limited to investigations of potential energy surfaces, enhance the
portfolio of computational methods applicable to NAs and offer considerably
more accurate intrinsic descriptions of NAs than standard MM. However,
in practice such calculations are hampered by the use of implicit
solvent environments and truncation of the systems. Conventional QM
optimizations are spoiled by spurious intramolecular interactions
and severe structural deformations. Here we compare two approaches
designed to suppress such artifacts: partially restrained continuum
solvent QM and explicit solvent QM/MM optimizations. We report geometry
relaxations of a set of diverse double-quartet guanine quadruplex
(GQ) DNA stems. Both methods provide neat structures without major
artifacts. However, each one also has distinct weaknesses. In restrained
optimizations, all errors in the target geometries (i.e., low-resolution
X-ray and NMR structures) are transferred to the optimized geometries.
In QM/MM, the initial solvent configuration causes some heterogeneity
in the geometries. Nevertheless, both approaches represent a decisive
step forward compared to conventional optimizations. We refine earlier
computations that revealed sizable differences in the relative energies
of GQ stems computed with AMBER MM and QM. We also explore the dependence
of the QM/MM results on the applied computational protocol.