ProCS15: a DFT-based chemical shift predictor for backbone and Cβatoms in proteins

Abstract

We present ProCS15: a program that computes the isotropic chemical shielding values of backbone and Cβ atoms given a protein structure in less than a second. ProCS15 is based on around 2.35 million OPBE/6-31G(d,p)//PM6 calculations on tripeptides and small structural models of hydrogen-bonding. The ProCS15-predicted chemical shielding values are compared to experimentally measured chemical shifts for Ubiquitin and the third IgG-binding domain of Protein G through linear regression and yield RMSD values of up to 2.2, 0.7, and 4.8 ppm for carbon, hydrogen, and nitrogen atoms. These RMSD values are very similar to corresponding RMSD values computed using OPBE/6-31G(d,p) for the entire structure for each proteins. These maximum RMSD values can be reduced by using NMR-derived structural ensembles of Ubiquitin. For example, for the largest ensemble the largest RMSD values are 1.7, 0.5, and 3.5 ppm for carbon, hydrogen, and nitrogen. The corresponding RMSD values predicted by several empirical chemical shift predictors range between 0.7–1.1, 0.2–0.4, and 1.8–2.8 ppm for carbon, hydrogen, and nitrogen atoms, respectively.

Protein structure refinement using a quantum mechanics-based chemical shielding predictor

“…The RMSD values are generally very similar to those computed previously for ubiquitin and protein GB3, 11 with the exception of N, where the average RMSD is 0.5 to 0.8 ppm lower. The r values for CA and CB are also quite similar to those obtained previously, but are significantly lower for the remaining nuclei.…”

“…The first row of Table 1 lists average RMSD and r values relative to experiments for chemical shift values computed using ProCS15 for 17 protein structures minimized using the CHARMM/CMAP force field. The RMSD values are generally very similar to those computed previously for ubiquitin and protein GB3, 11 with the exception of N, where the average RMSD is 0.5 to 0.8 ppm lower. The r values for CA and CB are also quite similar to those obtained previously, but are significantly lower for the remaining nuclei.…”

“…In this study we use ProCS15 ( ref. 11 ) to predict the corresponding isotropic chemical shielding value σ i , which we relate to δ ij by δ pred, ij = a j σ ij + b j …”

“…CamShift, 1 PPM_One, 2 Sparta+, 3 shAIC, 4 and ShiftX2, 5 are typically based on approximate physical models with adjustable parameters that are optimized by minimizing the discrepancy between experimental and predicted chemical shifts computed using protein structures derived from X-ray crystallography. Alternatively, protein chemical shifts can be predicted using computational quantum mechanics (QM), either indirectly using QM-derived models such as SHIFTS, 6 , 7 CheShift, 8 , 9 and ProCS, 10 , 11 or directly using QM/MM or linear scaling approaches. 12 – 15 …”

Combining Experimental Data and Computational Methods for the Non-Computer Specialist

“…There are several programs that predict CS based on a three-dimensional structure using different methods (for instance ProCS15 use DFT quantum mechanics [ 37 ]; SHIFTX2 [ 38 ], and SPARTA+ [ 39 ] use empirical approximations). And while there are usually higher discrepancies with the back-calculated H and N, most of them perform very well when computing the carbons chemical shifts.…”