PROST: AlphaFold2-aware sequence-based predictor to estimate protein stability changes upon missense mutations

Shahid Iqbal, Fang Ge, Fuyi Li, Tatsuya Akutsu, Yuanting Zheng, Robin B. Gasser, Dong Jun Yu, Geoffrey I. Webb, Jiangning Song

Research output: Contribution to journalArticleResearchpeer-review

31 Citations (Scopus)

Abstract

An essential step in engineering proteins and understanding disease-causing missense mutations is to accurately model protein stability changes when such mutations occur. Here, we developed a new sequence-based predictor for the protein stability (PROST) change (Gibb's free energy change, ΔΔG) upon a single-point missense mutation. PROST extracts multiple descriptors from the most promising sequence-based predictors, such as BoostDDG, SAAFEC-SEQ, and DDGun. RPOST also extracts descriptors from iFeature and AlphaFold2. The extracted descriptors include sequence-based features, physicochemical properties, evolutionary information, evolutionary-based physicochemical properties, and predicted structural features. The PROST predictor is a weighted average ensemble model based on extreme gradient boosting (XGBoost) decision trees and an extra-trees regressor; PROST is trained on both direct and hypothetical reverse mutations using the S5294 (S2647 direct mutations + S2647 inverse mutations). The parameters for the PROST model are optimized using grid searching with 5-fold cross-validation, and feature importance analysis unveils the most relevant features. The performance of PROST is evaluated in a blinded manner, employing nine distinct data sets and existing state-of-the-art sequence-based and structure-based predictors. This method consistently performs well on frataxin, S217, S349, Ssym, S669, Myoglobin, and CAGI5 data sets in blind tests and similarly to the state-of-the-art predictors for p53 and S276 data sets. When the performance of PROST is compared with the latest predictors such as BoostDDG, SAAFEC-SEQ, ACDC-NN-seq, and DDGun, PROST dominates these predictors. A case study of mutation scanning of the frataxin protein for nine wild-type residues demonstrates the utility of PROST. Taken together, these findings indicate that PROST is a well-suited predictor when no protein structural information is available. The source code of PROST, data sets, examples, and pretrained models along with how to use PROST are available at https://github.com/ShahidIqb/PROST and https://prost.erc.monash.edu/seq.

Original languageEnglish
Pages (from-to)4270–4282
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume62
Issue number17
DOIs
Publication statusPublished - 16 Aug 2022

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