Stability and solvation thermodynamics of proteins in mixed co-solvents

Structure and function of proteins in aqueous medium can be altered by the presence of cosolvents such as salts or osmolytes (osmoytes: small organic compounds which maintain cellular osmotic stress). Denaturing osmolytes such as urea or denaturing salts such as guanidinium chloride (GdmCl) destabilize the functional conformations of the cellular proteins. In contrast, protein protective osmolytes such as trimethylamine N-oxide (TMAO) stabilize proteins’ native structures. In cellular environment, proteins are exposed to mixtures of many cosolvents. In this talk, using molecular dynamics simulation and thermodynamical theory of solutions, I’ll discuss the stability and the conformational changes of proteins in two biologically relevant cosolvent mixtures: a) urea-TMAO (mixture of denaturing-protective osmolytes) and b) urea-GdmCl (mixture of two denaturants). First, I’ll demonstrate how TMAO counteracts urea-denaturation by effectively removing urea from protein surface. Then I’ll show how urea and GdmCl denature proteins via two distinctly different mechanisms and how GdmCl promotes urea-denaturation whereas urea disfavors GdmCl-denaturation in mixed urea-GdmCl solutions