Cover Story：Understanding and explaining how proteins fold have been the ultimate challenges in molecular and structure biology. Protein folding should initiate from a thermodynamic metastable state of unfolded proteins, otherwise, it is difficult to explain how an unfolded protein chain folds exactly into its native 3D structure in an expeditious and reproducible manner under severe thermal disturbance from temperature. Considering dependency of protein folding on aqueous environments and unique physical properties of water molecules, this study uncovers an initial thermodynamic metastable state of unfolded proteins in aqueous environment that enables them to that resists thermal-motion and avoids misfolding. The existence of the thermodynamic metastable state of unfolded proteins are verified by analyzing the results available from experiments in the literature. The principles of physics are applied to estimate the breakage of the thermodynamic metastable state of specific amino acids, that enable the leading to the inferred as physical folding mechanisms and codes for proteins.