Molecular Docking-Based Analysis Of TNNT2 Variants: A Computational Approach To Cardiomyopathy-Associated Mutations

Abstract

Heritable cardiomyopathies have been strongly linked to pathogenic variants in the TNNT2 gene [1], which encodes cardiac troponin T – a critical regulatory subunit of the troponin complex within the sarcomere. These mutations compromise the normal calcium-dependent regulatory mechanism of cardiac contraction by destabilizing the structural and functional integrity of the troponin-tropomyosin complex. Depending on their specific location and biochemical nature, TNNT2 mutations [2] may lead to altered calcium sensitivity, impaired contractile signaling, or sarcomeric disorganization. Such molecular perturbations are associated with divergent clinical outcomes, including hyper contractile phenotypes typical of hypertrophic cardiomyopathy [3] and hypo contractile states characteristic of dilated cardiomyopathy [4]. These changes not only reduce cardiac efficiency but also contribute to maladaptive remodeling, promoting arrythmogenic substrates and progressive cardiac dysfunction. In this investigation, we employ advanced computational strategies-specifically molecular docking and virtual screening-to identify novel small-molecule modulators that can potentially rectify the structural and functional deficits caused by disease-associated TNNT2 mutations.