Prediction of Intrinsic Disorder Using Rosetta ResidueDisorder and AlphaFold2.

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Abstract

The combination of deep learning and sequence data has transformed protein structure prediction and modeling, evidenced in the success of AlphaFold (AF). For this reason, many methods have been developed to take advantage of this success in areas where inaccurate structural modeling may limit computational predictiveness. For example, many methods have been developed to predict protein intrinsic disorder from sequence, including our Rosetta ResidueDisorder (RRD) approach. Intrinsically disordered regions in proteins are parts of the sequence that do not form ordered, folded structures under typical physiological conditions. In the original implementation of RRD, Rosetta ab initio models were generated, and disordered regions were predicted based on residue scores (disordered residues typically exist in regions of unfavorable scores). In this work, we show that by (i) replacing the ab initio modeling with AF (using the same scoring and disorder assignment approach) and (ii) updating the score function, the predictiveness improved significantly. Residues were better ranked by the order/disorder, evidenced by an improvement in receiver operating characteristic area-under-the-curve from 0.69 to 0.78 on a large (229 protein) and balanced data set (relatively even ordered versus disordered residues). Finally, the binary prediction accuracy also improved from 62% to 74% on the same data set. Our results show that the combined AF-RRD approach was as good as or better than all existing methods by these metrics (AF-RRD had the highest prediction accuracy).