Bottom-Up View of the Mechanism of Action of Protein-Stabilizing Osmolytes

Abstract

The molecular mechanism of osmolytes on the stabilization of native states of protein is still controversial irrespective of extensive studies over several decades. Recent investigations in terms of experiments and molecular dynamics simulations challenge the popular osmophobic model explaining the mechanistic action of protein-stabilizing osmolytes. The current Perspective presents an updated view on the mechanistic action of osmolytes in light of resurgence of interesting experiments and computer simulations over the past few years in this direction. In this regard, the Perspective adopts a bottom-up approach starting from hydrophobic interactions and eventually adds complexity in the system, going toward the protein, in a complex topology of hydrophobic and electrostatic interactions. Finally, the Perspective unifies osmolyte-induced protein conformational equilibria in terms of preferential interaction theory, irrespective of individual preferential binding or exclusion of osmolytes depending on different osmolytes and protein surfaces. The Perspective also identifies future research directions that can potentially shape this interesting area.

Associated Water Dynamics Might Be a Key Factor Affecting Protein Stability in the Crowded Milieu

“…This is probably the reason why such studies shifted to protein stability in osmolytes, in which protein structure remains almost unaltered. The mechanism of protein–osmolyte interaction is far more studied and understood and is often explained in terms of changes in the water structure and dynamics; − more precisely by a change in preferential hydration. Generally, the osmolytes are stabilizing (like sucrose and trehalose) and are preferentially accumulated at the protein solvent interface (i.e., water is preferentially included). − This theory turns out to be successful in explaining protein stabilization by adding solute almost accurately.…”

“…Generally, the osmolytes are stabilizing (like sucrose and trehalose) and are preferentially accumulated at the protein solvent interface (i.e., water is preferentially included). − This theory turns out to be successful in explaining protein stabilization by adding solute almost accurately. Despite a vast number of theoretical and simulation studies, only a few recent experimental papers have hinted at the importance of solvation in osmolyte-induced protein stabilization. − Havenith and co-workers studied water dynamics (using terahertz spectroscopy) in the presence of mono- and disaccharides. They found that disaccharides slow down the water dynamics to a greater extent than monosaccharides .…”

“…The mechanism of protein–osmolyte interaction is far more studied and understood and is often explained in terms of changes in the water structure and dynamics; − more precisely by a change in preferential hydration. Generally, the osmolytes are stabilizing (like sucrose and trehalose) and are preferentially accumulated at the protein solvent interface (i.e., water is preferentially included). − This theory turns out to be successful in explaining protein stabilization by adding solute almost accurately. Despite a vast number of theoretical and simulation studies, only a few recent experimental papers have hinted at the importance of solvation in osmolyte-induced protein stabilization. − Havenith and co-workers studied water dynamics (using terahertz spectroscopy) in the presence of mono- and disaccharides.…”

Influence of Aqueous Arginine Solution on Regulating Conformational Stability and Hydration Properties of the Secondary Structural Segments of a Protein at Elevated Temperatures: A Molecular Dynamics Study

“…The environment is naturally crowded by the cellular components, several other cosolvents, salts, etc. Cosolvents, like small sugars, polyols, alcohols, urea, etc., while present along with water, regulate the structural stability and function of proteins − by altering equilibria and kinetics of the process by interacting with the proteins either weakly or strongly compared to water. Majorly, two different classes of cosolvents, known as osmolytes (stabilizer) and denaturants, exist.…”

Virtual Issue on Protein Crowding and Stability

“…Based also on artificial crowders, it was furthermore analyzed how crowding effects on the structure of actin may lead to increased stiffness when forming filaments . Closely related are studies of peptides and proteins in the presence of different osmolytes such as TMAO, − trehalose, ethylene glycol, and ethanol, as they capture different aspects of the stabilizing and destabilizing molecules that may be encountered in cellular environments. Equally relevant are a number of mostly simulation studies that explore peptide and protein conformations in the presence of ionic liquids, − an area of increased interest in itself, as the organic ions present in these solvents also have parallels in biological environments.…”