Examining Genetic Variants Associated with FOXP1 Syndrome through Molecular Dynamics of Its DNA-Binding Domain and Self-Organizing Maps

Genetic mutations in the transcription factor FOXP1 (forkhead box protein P1) cause an autosomal dominant neurodevelopmental disorder called FOXP1 syndrome. To understand the structural impact of pathogenic variants associated with FOXP1 syndrome, we investigated the conformational changes resulting from six distinct missense variants in FOXP1 by combining molecular dynamics simulations, molecular docking, and machine learning via self-organizing maps. Our results reveal different conformational landscapes mapped by the FOXP1 variants and reduced interactions with the DNA for mutations residing in helix H3 of the DNA-binding domain. These analyses offer a framework for assessing the structural impact of missense variants implicated in the FOXP1 syndrome, highlighting the importance of structural inferences in interpreting genetic variants.