Protection of telomeres 1 (POT1) is a protein that plays an essential role in the shelterin complex by binding to the telomere and signaling the end of the chromosome. In our previous work, we demonstrated the effects of 3 melanoma-associated mutations on its ability to bind to ssDNA. Our collaborators tested 14057 variants through Saturation Genomic Editing and narrowed them to 2106 common clinical missense variants. In this work, we used classical MD simulations to investigate the effects of 20 different mutations to observe their effects on the dynamics, structure, and the binding affinity to telomeric DNA. Our results provide an insight on the difference between the cancer-associated variants and with the binding affinity, we were able to characterize two different phenotypes, which are in agreement with the experimental data.

<b>Differences in hydrogen bonding to the telomeric DNA and inter-molecular interactions between WT POT1 and cancer variants.</b><br /> Insets denote significant changes in hydrogen bonding interactions (dashed lines) with the telomeric DNA with respect to WT, and changes in the intermolecular interactions as calculated from energy decomposition analysis (EDA) with respect to the corresponding mutation of each variant. EDA results showed that K33, R273 and K247 were affected by the presence of the mutant. All data are mapped onto the respective variant structure.

Differences in hydrogen bonding to the telomeric DNA and inter-molecular interactions between WT POT1 and cancer variants.
Insets denote significant changes in hydrogen bonding interactions (dashed lines) with the telomeric DNA with respect to WT, and changes in the intermolecular interactions as calculated from energy decomposition analysis (EDA) with respect to the corresponding mutation of each variant. EDA results showed that K33, R273 and K247 were affected by the presence of the mutant. All data are mapped onto the respective variant structure.

David Adams

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