UCBShift 2.0: Bridging the Gap from Backbone to Side Chain Protein Chemical Shift Prediction for Protein Structures.

Chemical shifts are a readily obtainable NMR observable that can be measured with high accuracy, and because they are sensitive to conformational averages and the local molecular environment, they yield detailed information about protein structure in solution. To predict chemical shifts of protein structures, we introduced the UCBShift method that uniquely fuses a transfer prediction module, which employs sequence and structure alignments to select reference chemical shifts from an experimental database, with a machine learning model that uses carefully curated and physics-inspired features derived from X-ray crystal structures to predict backbone chemical shifts for proteins. In this work, we extend the UCBShift 1.0 method to side chain chemical shift prediction to perform whole protein analysis, which, when validated against well-defined test data shows higher accuracy and better reliability compared to the popular SHIFTX2 method. With the greater abundance of cleaned protein shift-structure data and the modularity of the general UCBShift algorithms, users can gain insight into different features important for residue-specific stabilizing interactions for protein backbone and side chain chemical shift prediction. We suggest several backward and forward applications of UCBShift 2.0 that can help validate AlphaFold structures and probe protein dynamics.