Hint approach on Transthyretin folding/unfolding mechanism comprehension

Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or temperature variations can compromise intramolecular stability generating misfolding or unfolding proteins with consequent impairment of functionality and the triggering of pathological states. The intramolecular HINT scoring function recently implemented and validated, is proposed as a rapid and sensitive method for the evaluation of different conformational states characterizing destabilization processes. In this work, the stability of Transthyretin, whose denaturation is related to amyloid fibril formation, is evaluated by generating multiple structural mutated models under different pH conditions in comparison with experimental data. These results suggest that the HINT scoring function can be used for an accurate and rapid evaluation and computational prediction of the effects of structural changes on any protein system.

Automated summary

Non-covalent intramolecular interactions are crucial for protein folding. Changes in amino acids, pH, or temperature can lead to misfolding or unfolding of proteins, resulting in functional impairment and pathological conditions. The recently implemented HINT scoring function is proposed as a rapid and sensitive method to evaluate destabilization processes. This study evaluates the stability of Transthyretin by generating mutated models under different pH conditions and comparing with experimental data, suggesting that the HINT scoring function can accurately and rapidly predict the effects of structural changes on protein systems.