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

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Authors

GKIONIS Konstantinos KRUSE Holger ŠPONER Jiří

Year of publication 2016
Type Article in Periodical
Magazine / Source Journal of Chemical Theory and Computation
MU Faculty or unit

Central European Institute of Technology

Citation
web http://pubs.acs.org/doi/full/10.1021/acs.jctc.5b01025
Doi http://dx.doi.org/10.1021/acs.jctc.5b01025
Field Physical chemistry and theoretical chemistry
Keywords MOLECULAR-DYNAMICS SIMULATIONS; QUANTUM-CHEMICAL COMPUTATIONS; CONTINUUM SOLVATION MODELS; DENSITY-FUNCTIONAL THEORY; SUGAR-PHOSPHATE BACKBONE; AIM TOPOLOGICAL ANALYSIS; TELOMERIC G-QUADRUPLEX; AB-INITIO CALCULATIONS
Description 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.
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