Accurate and Cost-Effective NMR Chemical Shift Predictions for Nucleic Acids Using a Molecules-in-Molecules Fragmentation-Based Method

Abstract

We have developed, implemented, and assessed an efficient protocol for the prediction of NMR chemical shifts of large nucleic acids using our molecules-in-molecules (MIM) fragment-based quantum chemical approach. To assess the performance of our approach, MIM-NMR calculations are calibrated on a test set of three nucleic acids, where the structure is derived from solution-phase NMR studies. For DNA systems with multiple conformers, the one-layer MIM method with trimer fragments (MIM1trimer) is benchmarked to get the lowest energy structure, with an average error of only 0.80 kcal/mol with respect to unfragmented full molecule calculations. The MIMI-NMRdimer calibration with respect to unfragmented full molecule calculations shows a mean absolute deviation (MAD) of 0.06 and 0.11 ppm, respectively, for 1H and 13C nuclei, but the performance with respect to experimental NMR chemical shifts is comparable to the more expensive MIM1-NMR and MIM2-NMR methods with trimer subsystems. To compare with the experimental chemical shifts, a standard protocol is derived using DNA systems with Protein Data Bank (PDB) IDs 1SY8, 1K2K, and 1KR8. The effect of structural minimizations is employed using a hybrid mechanics/semiempirical approach and used for computations in solution with implicit and explicit–implicit solvation models in our MIM1-NMRdimer methodology. To demonstrate the applicability of our protocol, we tested it on seven nucleic acids, including structures with nonstandard residues, heteroatom substitutions (F and B atoms), and side chain mutations with a size ranging from ∼300 to 1100 atoms. The major improvement for predicted MIM1-NMRdimer calculations is obtained from structural minimizations and implicit solvation effects. A significant improvement with the explicit–implicit solvation model is observed only for two smaller nucleic acid systems (1KR8 and 7NBK), where the expensive first solvation shell is replaced by the microsolvation model, in which a single water molecule is added for each solvent-exposed amino and imino protons, along with the implicit solvation. Overall, our target accuracy of ∼0.2–0.3 ppm for 1H and ∼2–3 ppm for 13C has been achieved for large nucleic acids. The proposed MIM-NMR approach is accurate and cost-effective (linear scaling with system size), and it can aid in the structural assignments of a wide range of complex biomolecules.

Approaching Coupled Cluster Accuracy with Density Functional Theory Using the Generalized Connectivity-Based Hierarchy

“…While coarse-grained CBH, briefly discussed in the final section, is a possible strategy, a general fragmentation approach gives much more flexibility in the generation of fragments of different sizes to optimize the accuracy and applicability of the calculations. Thus, we have carried out calculations on biological systems containing well over a thousand atoms , using our MIM fragmentation method.…”

MIM-ML: A Novel Quantum Chemical Fragment-Based Random Forest Model for Accurate Prediction of NMR Chemical Shifts of Nucleic Acids

“…The MIM-NMR calculated chemical shifts are taken from our previous study on 10 nucleic acids. 49 We used "dimer" primary subsystems that incorporate stacking interactions between adjacent units, defined by the fragmentation parameter (r), calculated with the selected high level of theory (vide inf ra). The derivative subsystems to account for the overcounting are then the corresponding "monomer" units.…”

“…56 The MIM1 microsolavtion -NMR model is efficient and was applied recently to a test set of 10 nucleic acids, including some nonstandard systems containing B and F atoms, to achieve a target performance of 0.3 ppm for 1 H and 2−3 ppm for 13 C chemical shifts, similar in magnitude to the values obtained previously on a variety of protein systems. 48,49 We train our ML model on this set of nucleic acids, as described in the next section.…”

Size-Reduced Basis Set Calculation of Accurate Isotropic Nuclear Magnetic Shieldings Using CTOCD-GRRO and GPRO Methods in Amino Acids and Oligopeptides

“…As far as it concerns the class of molecules, we thought that the set of 20 naturally occurring L-α-amino acids represents a quite convenient choice, due to the variety of nuclei and the possibility to consider further oligopeptides, as, for example, glutathione (GSH), ophthalmic acid (OPH), and thyrotropin-releasing hormone (TRH). In this context, the molecules-in-molecules fragmentation-based method applied to proteins and nucleic acids is noteworthy. In the following, we will describe the new method of calculation and the excellent results obtained, along with a way to compute the nuclear magnetic shieldings for all the nuclei of a molecule on the fly by means of Becke’s algorithm .…”