Predicting protein flexibility with AlphaFold

Abstract

AlphaFold2 has revolutionized protein structure prediction from amino-acid sequence. In addition to protein structures, high-resolution dynamics information about various protein regions is important for understanding protein function. Although AlphaFold2 has neither been designed nor trained to predict protein dynamics, it is shown here how the information returned by AlphaFold2 can be used to predict dynamic protein regions at the individual residue level. The approach, which is termed cdsAF2, uses the 3D protein structure returned by AlphaFold2 to predict backbone NMR NH S² order parameters using a local contact model that takes into account the contacts made by each peptide plane along the backbone with its environment. By combining for each residue AlphaFold2's pLDDT confidence score for the structure prediction accuracy with the predicted S² value using the local contact model, an estimator is obtained that semi-quantitatively captures many of the dynamics features observed in experimental backbone NMR NH S² order parameter profiles. The method is demonstrated for a set nine proteins of different sizes and variable amounts of dynamics and disorder.

Keywords: AlphaFold; AlphaFold2; NMR dynamics; backbone NMR NH S2 order parameters; contact model; prediction of protein flexibility and dynamics; protein structure prediction.