I131T Mutation’s Effects on Van der Waals Forces and Solvation Energy in Congenital Hypothyroidism

Abstract

Garcia et al. (2017) unraveled the intricate mechanisms underlying the impact of the p.I131T mutation on the Thyrotropin Releasing Hormone Receptor (TRHR), a class A G-protein coupled receptor (GPCR). This mutation leads to Congenital Hypothyroidism in an 8-year-old patient with homozygosity and Hyperthyrotropinemia in heterozygous family members. The mutation substitutes a polar Thr for a non-polar Ile, disrupting the hydrophobic pocket within the TRHR-G-protein interface. While Molecular Dynamics (MD) simulations unveiled this interaction, the absence of experimental data on the activated TRH-TRHR-G protein complex hindered a comprehensive assessment. Addressing this gap, when Youwei Xu et al. (2022) recently presented the Cryo-EM structure of the activated complex, we employed Rosetta (Alford, et al., 2017) to optimize this structure and generated 100 starting structures; the five best ones were used as starting template structures to produce protein structures for both wild-type and mutant TRHR-TRH-G protein complexes. Our study not only validated Garcia et al.’s findings on reduced signal transduction but also pinpointed critical chemical interactions affected by the p.I131T mutation—specifically, Van der Waals forces and Solvation energy.