Novel Pathogenic Variant in TGFBR2 Confirmed by Molecular Modeling Is a Rare Cause of Loeys-Dietz Syndrome

Figure 1

Molecular modeling of the L354P mutation reveals alteration of local structure leading to changes in flexibility. (a) The TGFBR2 kinase domain structure is shown in a blue cartoon representation with amino acid position 354 marked by a red sphere and an adenosine placed in the ATP binding pocket shown as ball-and-stick. Representatives from the beginning of our MD simulation are shown as white backbone trace. (b) Root Mean Squared Fluctuations (RMSF) capture the flexibility of the protein and are plotted for the mutant and wt simulations. Regions with largest difference are highlighted (colored similarly in (a)) and position 354 is marked with an asterisk. (c) During our simulation, the local helical structure around L354P is destabilized and unwinds, pushing the rest of the helix into an altered conformation.

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