Computational Analysis of TSHb Variants (Native, Mutated and Deleted) in Interaction with TSHR: Molecular Docking and Dynamic Simulations for Mechanistic Insights into Congenital Hypothyroidism

Thyroid Stimulating Hormone (TSH) is a primary protein and biomarker for the early detection of congenital hypothyroidism (CH). CH poses a serious risk for newborns as it can lead to neurological development issues, motor skill delays, and lower IQ. This study aims to computationally compare the interaction effectiveness of TSHb (native, mutation, deletion) with TSHR (Thyroid Stimulating Hormone Receptor). TSHb were constructed based on the 3D structures of fPDB proteins, specifically 7FIH_Y, 6P57_A, 6P57_B, 1HCN_B, and 1QFW_B. TSH and TSHR models were obtained from the RSCB PDB (ID: 7XW5). Molecular dynamics simulations were conducted using YASARA Dynamics. Potential energy, SASA, hydrogen bonds within the solute, hydrogen bonds between solute and solvent, RMSD, and radius of gyration analyses were obtained through the md_analyze macro. Docking and molecular dynamics simulations revealed that mutations and deletions in TSHb impact its stability, functionality, and interactions with TSHR. Furthermore, significant structural changes and reduced conformational stability were observed in the TSHb variant with a nucleotide deletion at position 114. However, this TSHb deletion variant did not alter the amino acid sequence of the active site for binding with TSHR. It is believed that this deletion variant retains sufficient affinity interaction with TSHR compared to the native TSHb. HIGHLIGHTS TSHb-TSHR Interaction: Mutations and deletions affect stability and thyroid function. Key Mutation Insight: TSHb deletion at position 114 alters structure but retains binding. Molecular Dynamics: Analyzed stability via energy, SASA, hydrogen bonds, and RMSD. Computational Modeling: Aids precision medicine for thyroid-related disorders. GRAPHICAL ABSTRACT