Accurate ab initio prediction of NMR chemical shifts of nucleic acids and nucleic acids/protein complexes

Abstract

NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3–0.6 ppm and correlation coefficients (r2) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization.

AFNMR: automated fragmentation quantum mechanical calculation of NMR chemical shifts for biomolecules

“…Scheurer and co-workers used DFT calculations on manually-generated fragments to compute chemical shielding anisotropy tensors (Scheurer et al, 1999). Exner and co-workers calculated the chemical shifts using the fragment based adjustable density matrix assembler (ADMA) method (Dracinsky et al, 2013,Exner et al, 2012,Frank et al, 2011,Victora et al, 2014). Gao et al also have used the fragment molecular orbital (FMO) method for protein NMR chemical shift calculations.…”

Accurate ab initio calculations of O–H⋯O and O–H⋯−O proton chemical shifts: towards elucidation of the nature of the hydrogen bond and prediction of hydrogen bond distances

“…38 (6) REDOR experiments, which are an attractive tool for studies of hydrogen bonding in the solid. [43][44][45][46][47][48] We report therein computed 1 H chemical shifts of a large set of thirtyfive compounds exhibiting intramolecular O-H⋯O hydrogen bond and eight compounds exhibiting strong intramolecular and intermolecular ionic O-H⋯ − O hydrogen bonds with the combined use of DFT and conductor-like polarized continuum model (PCM) theory in CHCl 3 . 40 In recent years, developments in first-principles methods for calculating NMR parameters, with particular emphasis on chemical shifts 41,42 as well as advances in computer power, have led to an increasing number of studies that combine calculation and experiment, thus allowing systematic investigations of hydrogen-bonding interactions.…”

Automated Fragmentation QM/MM Calculation of NMR Chemical Shifts for Protein-Ligand Complexes

“…The quantum mechanical chemical shift calculations are in principle able to predict the NMR chemical shifts for any complex systems (Lodewyk et al, 2012 ; Hartman and Beran, 2014 ; Merz, 2014 ). For protein NMR chemical shift calculations, Cui and Karplus had proposed a very effective QM/MM approach (Cui and Karplus, 2000 ), Gao et al developed fragment molecular orbital (FMO) method (Gao et al, 2007 , 2010 ), Exner and coworkers utilized the adjustable density matrix assembler (ADMA) approach (Frank et al, 2012 ; Victora et al, 2014 ), Tan and Bettens developed the combined fragmentation method (CFM) (Tan and Bettens, 2013 ), and He and coworkers developed the automated fragmentation quantum mechanics/molecular mechanics (AF-QM/MM) method (He et al, 2009 , 2014 ; Zhu et al, 2012 , 2013 , 2014 , 2015 ; Swails et al, 2015 ; Jin et al, 2016 ) These fragment-based QM methods have been successfully applied for NMR chemical shift calculation of proteins and nucleic acids.…”