BACKGROUND: The bHLH transcription factor TWIST1 plays a key role in the 
embryonic development and in tumorigenesis. Some loss-of-function mutations of 
the TWIST1 gene have been shown to cause an autosomal dominant craniosynostosis, 
known as the Saethre-Chotzen syndrome (SCS). Although the functional impacts of 
many TWIST1 mutations have been experimentally reported, little is known on the 
molecular mechanisms underlying their loss-of-function. In a previous study, we 
highlighted the predictive value of in silico molecular dynamics (MD) 
simulations in deciphering the molecular function of TWIST1 residues.
RESULTS: Here, since the substitution of the arginine 154 amino acid by a 
glycine residue (R154G) is responsible for the SCS phenotype and the 
substitution of arginine 154 by a proline experimentally decreases the 
dimerizing ability of TWIST1, we investigated the molecular impact of this point 
mutation using MD approaches. Consistently, MD simulations highlighted a clear 
decrease in the stability of the α-helix during the dimerization of the mutated 
R154P TWIST1/E12 dimer compared to the wild-type TE complex, which was further 
confirmed in vitro using immunoassays.
CONCLUSIONS: Our study demonstrates that MD simulations provide a structural 
explanation for the loss-of-function associated with the SCS TWIST1 mutation and 
provides a proof of concept of the predictive value of these MD simulations. 
This in silico methodology could be used to determine reliable pharmacophore 
sites, leading to the application of docking approaches in order to identify 
specific inhibitors of TWIST1 complexes.