Protein Structure Prediction to Understand Pathogenicity
Understanding and predicting the change of protein structure and function upon mutation and its relationship to human health is a critical element to translate the genomic revolution into actionable interventions. As an example, missense mutations that cause protein misfolding and/or changes in physicochemical properties of protein involved in metabolic pathways, e.g. tumor suppression, cell cycle checkpoints, and DNA repair, are a well-known cause of oncogenesis. However, since the effects of mutations on structural properties of proteins are multifactorial, predictions concerning these effects (i.e. pathogenic/not pathogenic) are not straightforward. Moreover, there is very limited experimental structural data for proteins in general and much less for the mutated species. Because the protein structure determination gap does not show any signs of amelioration, using computational methods to study this problem appears worthwhile exploring. This approach is also strongly supported by recent advances in computational resources and methods to predict 3D protein structures.
Exemplar Publications
- Teerlink, C.C., Stevens, J., Hernandez, R., Facelli, J.C., Cannon-Albright, L.A. An intronic variant in the CELF4 gene is associated with risk for colorectal cancer (2021) Cancer Epidemiology, 72, art. no. 101941
- Cannon-Albright LA, Teerlink CC, Stevens J, Facelli JC, Carr SR, Allen-Brady K, et al. A rare FGF5 candidate variant (rs112475347) for predisposition to nonsquamous, nonsmall-cell lung cancer. International journal of cancer. 2023;153(2):364-72..
- Li, C., Liu, T., Liu, B., Hernandez, R., Facelli, J.C., Grossman, D ; A novel CDKN2A variant (p16L117P) in a patient with familial and multiple primary melanomas (2019) Pigment Cell and Melanoma Research, 32 (5), pp. 734-738.
- Cannon-Albright LA, Stevens J, Teerlink CC, Facelli JC, Allen-Brady K, Welm AL. A rare variant in MDH2 (rs111879470) is associated with predisposition to recurrent breast cancer in an extended high-risk pedigree. Cancers. 2023;15(24):5851.
- Albano JMR, Mussini N, Toriano R., Facelli JC, Ferraro MB, Pickholz M (2018). Calcium interactions with Cx26 hemmichannel: Spatial association between MD simulations biding sites and variant pathogenicity. Computational Biology and Chemistry, 77, pp. 331-342.
- Teerlink CC, Huff C, Stevens J, Yu Y, Holmen SL, Silvis MR, Trombetti K, Zhao H, Grossman D, Farnham JM, Wen J, Facelli JC, Thomas A, Babst M, Florell S., Meyer L, Zone JJ, Leachman S, Cannon-Albright LA (2018). A Nonsynonymous Variant in the GOLM1 Gene in Cutaneous Malignant Melanoma. Journal of the National Cancer Institute, 110 (12), pp. 1380-1385.