MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex

Abstract

A generalization of the Moving-Domain Quantum Mechanics/Molecular Mechanics (MoD-QM/MM) hybrid method [Gascon, J. A.; Leung, S. S. F.; Batista, E. R.; Batista, V. S. J. Chem. Theory Comput. 2006, 2, 175– 186] is introduced to provide a self-consistent computational protocol for structural refinement of extended systems. The method partitions the system into molecular domains that are iteratively optimized as quantum mechanical (QM) layers embedded in their surrounding molecular environment to obtain an ab initio quality description of the geometry and the molecular electrostatic potential of the extended system composed of those constituent fragments. The resulting methodology is benchmarked as applied to model systems that allow for full QM optimization as well as through refinement of the hydrogen bonding geometry in Oxytricha nova guanine quadruplex for which several studies have been reported, including the X-ray structure and NMR data. Calculations of 1H NMR chemical shifts based on the gauge independent atomic orbital (GIAO) method and direct comparisons with experiments show that solvated MoD-QM/MM structures, sampled from explicit solvent molecular dynamics simulations, allow for NMR simulations in much improved agreement with experimental data than models based on the X-ray structure or those optimized using classical molecular mechanics force fields.

The MOD-QM/MM Method

“…The resulting computational task scales linearly with the size of the system, bypassing the exponential demand of memory and computational resources typically required by “brute-force” full QM calculations. Computations for several benchmark systems that allow for full QM calculations have shown that the MOD-QM/MM method produces ab initio quality structures and ESPs in quantitative agreement with full QM results (Gascon, Leung, et al, 2006; Ho et al, 2014; Menikarachchi & Gascon, 2008; Sandberg et al, 2012). The work reviewed in this chapter illustrates the MOD-QM/MM method as applied to the description of macromolecules of biological interest, including PSII and DNA quadruplexes, in conjunction with structural refinement based on simulations of X-ray absorption spectra and direct comparisons with experimental data.…”

“…In the MOD-QM/MM method, the system is partitioned into n molecular domains using a simple space-domain decomposition scheme (Gascon, Leung, et al, 2006; Ho et al, 2014; Menikarachchi & Gascon, 2008). A two-layer QM/MM scheme is used to optimize the geometry of each molecular domain and to compute the electrostatic potential (RESP) atomic charges of each fragment as influenced by the surrounding molecular environment.…”

“…QM/MM methods significantly expand the scope of quantum mechanical calculations to much larger systems by limiting the quantum mechanical description (typically based on density functional theory (DFT)) to a subsystem where chemical reactivity is localized (QM layer), while the “spectator” region is usually treated with an inexpensive model chemistry such as classical molecular mechanics force fields, or a lower level of electronic structure theory (eg, semiempirical methods). This partitioning scheme ensures highly efficient, yet accurate, modeling of electrostatic interactions as exploited by the Moving-Domain QM/MM (MOD-QM/MM) methodology (Gascon, Leung, Batista, & Batista, 2006; Ho et al, 2014; Menikarachchi & Gascon, 2008; Sandberg, Rudnitskaya, & Gascón, 2012) and the studies of the oxygen-evolving complex (OEC) of photosystem II (PSII) reviewed in this chapter.…”

“…In the electronic embedding approach, the atom-centered point charges in the MM layer can polarize the QM electronic density. Finally, higher-level corrections to include the mutual polarization between the MM and QM layers can be included in the polarized embedding scheme (Devries et al, 1995; Eichler, Kolmel, & Sauer, 1997; Gao & Xia, 1992; Thompson, 1996; Vreven, Mennucci, da Silva, Morokuma, & Tomasi, 2001), and in the MOD-QM/MM scheme (Gascon, Leung, et al, 2006; Ho et al, 2014; Menikarachchi & Gascon, 2008). …”

“…The MOD-QM/MM method partitions the system into molecular domains and obtains the geometry and electrostatic properties of the whole system from an iterative self-consistent treatment of the constituent molecular domains (Gascon, Leung, et al, 2006; Ho et al, 2014; Menikarachchi & Gascon, 2008; Sandberg et al, 2012). Self-consistently optimized structures and electrostatic potential (ESP) atomic charges are obtained for each domain modeled as a QM layer polarized by the distribution of atomic charges in the surrounding fragments.…”