Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics

The growing availability of protein structural data from experimental methods and accurate predictive models provides the opportunity to investigate the molecular origins of rare diseases (RDs) reviewed in the Orpha.net database. In this study, we analyzed the topology of 5728 missense mutation sites involved in Mendelian RDs (MRDs), forming the basis of our structural bioinformatics investigation. Each mutation site was characterized by side-chain position within the overall 3D protein structure and side-chain orientation. Atom depth quantitation, achieved by using SADIC v2.0, allowed the classification of all the mutation sites listed in our database. Particular attention was given to mutations where smaller amino acids replaced bulky, outward-oriented residues in the outer structural layers. Our findings reveal that structural features that could lead to the formation of void spaces in the outer protein region are very frequent. Notably, we identified 722 cases where MRD-associated mutations could generate new surface pockets with the potential to accommodate pharmaceutical ligands. Molecular dynamics (MD) simulations further supported the prevalence of cryptic pocket formation in a subset of drug-binding protein candidates, underscoring their potential for structure-based drug discovery in RDs.