Structurally different chemical chaperones show similar mechanical roles with independent molecular mechanisms.

Osmolytes are well known to protect the protein structure against different chemical and physical denaturants. Since their actions with protein surfaces are mechanistically complicated and context dependent, the underlying molecular mechanism is not fully understood. Here, we combined single-molecule magnetic tweezers and molecular dynamics (MD) simulation to explore the mechanical role of osmolytes from two different classes, trimethylamine -oxide (TMAO) and trehalose, as mechanical stabilizers of protein structure.