Metamorphic proteins can switch between multiple native states, challenging the traditional view that proteins have a single, unique structure. Recent studies have identified over 100 such proteins across all life forms, showing that they can reversibly interconvert between different folds. These proteins play important roles in regulating biological functions, as demonstrated by examples like RfaH, KaiB, and CLIC1. Structural biology methods have confirmed the existence of these proteins by solving their structures under different conditions, but they have not fully elucidated the mechanisms of their interconversion. Computational methods, such as dual-basin structure-based models (SBMs), have been used to simulate the refolding processes of metamorphic proteins. These models simplify the complex interactions between amino acids, allowing for more efficient simulations. SBMs have been applied to various fold-switching proteins, revealing that they often pass through intermediate states that retain some native-like structure. Additionally, experimental biophysics techniques like NMR and HDX-MS have been used to study the structural changes and timescales of these proteins. These methods have shown that the refolding timescales can vary from seconds to hours. AI-based protein structure prediction methods, such as AlphaFold2, have struggled to accurately predict the structures of metamorphic proteins, highlighting the need for further research and improved computational approaches. Experimental assays are also needed to identify and characterize new fold-switching proteins, which can then be used to train more accurate AI models. Overall, the study of metamorphic proteins is an active area of research with important implications for understanding protein function and evolution.Metamorphic proteins can switch between multiple native states, challenging the traditional view that proteins have a single, unique structure. Recent studies have identified over 100 such proteins across all life forms, showing that they can reversibly interconvert between different folds. These proteins play important roles in regulating biological functions, as demonstrated by examples like RfaH, KaiB, and CLIC1. Structural biology methods have confirmed the existence of these proteins by solving their structures under different conditions, but they have not fully elucidated the mechanisms of their interconversion. Computational methods, such as dual-basin structure-based models (SBMs), have been used to simulate the refolding processes of metamorphic proteins. These models simplify the complex interactions between amino acids, allowing for more efficient simulations. SBMs have been applied to various fold-switching proteins, revealing that they often pass through intermediate states that retain some native-like structure. Additionally, experimental biophysics techniques like NMR and HDX-MS have been used to study the structural changes and timescales of these proteins. These methods have shown that the refolding timescales can vary from seconds to hours. AI-based protein structure prediction methods, such as AlphaFold2, have struggled to accurately predict the structures of metamorphic proteins, highlighting the need for further research and improved computational approaches. Experimental assays are also needed to identify and characterize new fold-switching proteins, which can then be used to train more accurate AI models. Overall, the study of metamorphic proteins is an active area of research with important implications for understanding protein function and evolution.