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

Visibelli, Anna; Finetti, Rebecca; Niccolai, Piero; Trezza, Alfonso; Spiga, Ottavia; Santucci, Annalisa; Niccolai, Neri

doi:10.3390/ijms26094072

Open AccessArticle

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

by

Anna Visibelli

^1,†

,

Rebecca Finetti

^1,†

,

Piero Niccolai

²,

Alfonso Trezza

¹,

Ottavia Spiga

^1,3

,

Annalisa Santucci

^1,3,*

and

Neri Niccolai

^1,2

¹

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy

²

Le Ricerche del BarLume Free Association, Ville di Corsano, Monteroni d’Arbia, 53014 Siena, Italy

³

Industry 4.0 Competence Center ARTES 4.0 Viale Rinaldo Piaggio, 56025 Pontedera, Italy

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(9), 4072; https://doi.org/10.3390/ijms26094072

Submission received: 3 April 2025 / Revised: 23 April 2025 / Accepted: 23 April 2025 / Published: 25 April 2025

(This article belongs to the Special Issue Molecular Dynamics Simulations of Protein Structures)

Download

Browse Figures

Versions Notes

Abstract

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.

Keywords: rare diseases; missense mutations; protein structure; molecular dynamics; structural bioinformatics

Graphical Abstract

Share and Cite

MDPI and ACS Style

Visibelli, A.; Finetti, R.; Niccolai, P.; Trezza, A.; Spiga, O.; Santucci, A.; Niccolai, N. Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics. Int. J. Mol. Sci. 2025, 26, 4072. https://doi.org/10.3390/ijms26094072

AMA Style

Visibelli A, Finetti R, Niccolai P, Trezza A, Spiga O, Santucci A, Niccolai N. Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics. International Journal of Molecular Sciences. 2025; 26(9):4072. https://doi.org/10.3390/ijms26094072

Chicago/Turabian Style

Visibelli, Anna, Rebecca Finetti, Piero Niccolai, Alfonso Trezza, Ottavia Spiga, Annalisa Santucci, and Neri Niccolai. 2025. "Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics" International Journal of Molecular Sciences 26, no. 9: 4072. https://doi.org/10.3390/ijms26094072

APA Style

Visibelli, A., Finetti, R., Niccolai, P., Trezza, A., Spiga, O., Santucci, A., & Niccolai, N. (2025). Profiling of Protein-Coding Missense Mutations in Mendelian Rare Diseases: Clues from Structural Bioinformatics. International Journal of Molecular Sciences, 26(9), 4072. https://doi.org/10.3390/ijms26094072

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

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

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI