Integration of a Randomized Sequence Scanning Approach in AlphaFold2 and Local Frustration Profiling of Conformational States Enable Interpretable Atomistic Characterization of Conformational Ensembles and Detection of Hidden Allosteric States in the ABL1 Protein Kinase.

Autor:	Raisinghani N; Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States., Alshahrani M; Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States., Gupta G; Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States., Tian H; Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas 75275, United States., Xiao S; Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas 75275, United States., Tao P; Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas 75275, United States., Verkhivker GM; Keck Center for Science and Engineering, Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, California 92866, United States.; Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California 92618, United States.; Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Jazyk:	angličtina
Zdroj:	Journal of chemical theory and computation [J Chem Theory Comput] 2024 Jun 25; Vol. 20 (12), pp. 5317-5336. Date of Electronic Publication: 2024 Jun 12.
DOI:	10.1021/acs.jctc.4c00222
Abstrakt:	Despite the success of AlphaFold methods in predicting single protein structures, these methods showed intrinsic limitations in the characterization of multiple functional conformations of allosteric proteins. The recent NMR-based structural determination of the unbound ABL kinase in the active state and discovery of the inactive low-populated functional conformations that are unique for ABL kinase present an ideal challenge for the AlphaFold2 approaches. In the current study, we employ several adaptations of the AlphaFold2 methodology to predict protein conformational ensembles and allosteric states of the ABL kinase including randomized alanine sequence scanning combined with the multiple sequence alignment subsampling proposed in this study. We show that the proposed new AlphaFold2 adaptation combined with local frustration profiling of conformational states enables accurate prediction of the protein kinase structures and conformational ensembles, also offering a robust approach for interpretable characterization of the AlphaFold2 predictions and detection of hidden allosteric states. We found that the large high frustration residue clusters are uniquely characteristic of the low-populated, fully inactive ABL form and can define energetically frustrated cracking sites of conformational transitions, presenting difficult targets for AlphaFold2. The results of this study uncovered previously unappreciated fundamental connections between local frustration profiles of the functional allosteric states and the ability of AlphaFold2 methods to predict protein structural ensembles of the active and inactive states. This study showed that integration of the randomized sequence scanning adaptation of AlphaFold2 with a robust landscape-based analysis allows for interpretable atomistic predictions and characterization of protein conformational ensembles, providing a physical basis for the successes and limitations of current AlphaFold2 methods in detecting functional allosteric states that play a significant role in protein kinase regulation.
Databáze:	MEDLINE
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