| Summary: | Personalized medicine, based on individual genetics, has advanced thanks to our understanding of the human genome and the exponential growth of recent biological data. Currently, treatments can be tailored to patients, improving precision in healthcare. In this regard, bioinformatics is essential for converting biological data into useful information, developing strategies to analyze large-scale data. Structural bioinformatics focuses on the three-dimensional analysis of biomolecules to facilitate the understanding of their biological function. This approach allows evaluating the impact of genetic variants and predicting responses to treatments, leading to more precise therapies (precision medicine). To illustrate the utility of these disciplines, let's consider a case reported in 2021 by Martin M. and collaborators. In this study, a patient was diagnosed with congenital hypothyroidism after validating a new mechanism mediated by the SLC5A5 gene, which encodes the membrane transporter protein (NIS). Initially, although the patient had mild symptoms, molecular analyses only detected the G561E variant in NIS. At that time, the cause of the disease could not be identified because the variant was not recorded in any database, and sequence-based predictors categorized it as benign. Martin et al. found that the variant was near the interaction domain with kinesins KLC2 and that it was affected by increased stability in alpha helices formed by the mutant, resulting in a lack of activity. This mechanism was experimentally validated. In 2018, Radusky and collaborators developed VarQ, a web server that analyzes genetic variants from a structural perspective. VarQ explains how a specific variant can contribute to a disease by evaluating structural parameters such as Gibbs free energy (ΔΔG), protein-protein interactions, modifications in the three-dimensional structure, and aggregation capacity, among others. Although structural parameters can attribute some pathogenicity to the variant, VarQ did not include the mechanism described by Martin M. and collaborators at that time, and there was no three-dimensional structure available for the human NIS protein on the server. For this reason, we created several models of NIS and calculated the same parameters as VarQ. The results showed that the secondary structure remained unchanged, and the ΔΔG values were negative, consistent with the findings of Martin M. and collaborators. Although this condition was not implemented in the VarQ algorithm, the information proved useful for classifying the variant. This study exemplifies how bioinformatics can be useful even when mutations have not been previously documented, highlighting its importance in modern medicine. Bioinformatics and structural analysis emerge as fundamental tools for providing precise answers and guiding clinical decisions.
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Bioinformatics in Biomedical Analysis and its impact on Personalized Medicine