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Characterization of the conformational alterations involved in monomer misfolding is essential for elucidating the molecular basis of the initial stage of protein accumulation. Here, we report the first structural analyses of transthyretin (TTR) (26−57) fragments with two histidine tautomeric states (δ; N δ1 H and ε; N ε2 H) using replica-exchange molecular dynamics (REMD) simulations. Explaining the organizational properties and misfolding procedure is challenging because the δ and ε configurations can occur in the free neutral state. REMD revealed that β-sheet generation is favored for the δδ (16.8%) and εδ (6.7%) tautomeric isomers, showing frequent main-chain contacts between the stable regions near the head (N-terminus) and central (middle) part compared to the εε (4.8%) and δε (2.8%) isomers. The presence of smaller and wider local energy minima may be related to the structural stability and toxicity of δδ/εδ and εε/δε. Histidines31 and 56 were the parts of regular (such as β-strand) and nonregular (such as coil) secondary structures within the highly toxic TTR isomer. For TTR amyloidosis, focusing on hazardous isomeric forms with high sheet contents may be a potent treatment strategy. Overall, our findings support the tautomerism concept and aid in our comprehension of the basic tautomeric actions of neutral histidine throughout the misfolding process. [Display omitted] • Histidine tautomerism can influence the structural and misfolding properties of the monomeric TTR (26−57). • δδ and εδ tautomeric isomers are more likely to form β-sheets than εε and δε. • A potent therapeutic strategy for TTR amyloidosis may be to target toxic tautomeric states. • This study will help in developing effective therapeutic agents for the treatment of TTR-related amyloid diseases. [ABSTRACT FROM AUTHOR]