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Classification of PTEN missense VUS through exascale simulations
Siddharth Sinha1, Jiaheng Li1, Benjamin Tam1
1Ministry of Education Frontiers Science Center for Precision Oncology, Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau S.A.R, China.
Briefings in Bioinformatics
|October 16, 2023
Summary
Computational simulations classified 147 PTEN variants of uncertain significance (VUS) into deleterious and tolerated groups. This functional evidence aids in understanding PTEN’s role in cancer and clinical variant interpretation.
Area of Science:
- Genomics and Bioinformatics
- Molecular Biology
- Computational Biology
Background:
- Phosphatase and tensin homolog (PTEN) is a tumor suppressor crucial for the PI3K/AKT pathway.
- Germline PTEN variations can increase cancer risk by impairing its phosphatase activity.
- Many PTEN variants are classified as variants of uncertain significance (VUS) due to a lack of functional data.
Purpose of the Study:
- To functionally classify 147 PTEN missense variants of uncertain significance (VUS).
- To investigate the impact of these VUS on PTEN's structural integrity and phosphatase activity.
- To provide evidence for clinical applications in PTEN-related cancers.
Main Methods:
- Employed Molecular Dynamics (MD) and Replica Exchange Molecular Dynamics (REMD) simulations.
- Analyzed 147 PTEN missense VUS, focusing on variants within the catalytic core of the phosphatase domain.
- Classified variants by assessing their effects on structural stability and conformational changes.
Main Results:
- Successfully classified 147 PTEN missense VUS into 66 deleterious and 81 tolerated variants.
- Identified conformational alterations affecting the structural stability of the PTEN phosphatase domain.
- Demonstrated high concordance with existing experimental and clinical classifications.
Conclusions:
- MD and REMD simulations are effective tools for functional PTEN VUS classification.
- This classification provides critical insights into PTEN's role in cancer pathogenesis.
- The findings will aid in the clinical interpretation of PTEN variants and patient risk assessment.
Keywords:
MD simulationsPTENevolution selectionlipid phosphatase activityreplica exchange molecular dynamics (REMD) simulationsvariants of uncertain significance (VUS)
