Balance of enthalpy and entropy in depletion forces

Abstract

Solutes added to solutions often dramatically impact molecular processes ranging from the suspension or precipitation of colloids to biomolecular associations and protein folding. Here we revisit the origins of the effective attractive interactions that emerge between and within macromolecules immersed in solutions containing cosolutes that are preferentially excluded from the macromolecular interfaces. Until recently, these depletion forces were considered to be entropic in nature, resulting primarily from the tendency to increase the space available to the cosolute. However, recent experimental evidence indicates the existence of additional, energetically-dominated mechanisms. In this review we follow the emerging characteristics of these different mechanisms. By compiling a set of available thermodynamic data for processes ranging from protein folding to protein-protein interactions, we show that excluded cosolutes can act through two distinct mechanisms that correlate to a large extent with their molecular properties. For many polymers at low to moderate concentrations the steric interactions and molecular crowding effects dominate, and the mechanism is entropic. To contrast, for many small excluded solutes, such as naturally occurring osmolytes, the mechanism is dominated by favorable enthalpy, whereas the entropic contribution is typically unfavorable. We review the available models for these thermodynamic mechanisms, and comment on the need for new models that would be able to explain the full range of observed depletion forces.Comment: 18 pages, 4 figures, supplementary info include

Analysis of the size dependence of macromolecular crowding shows that smaller is better

“…The implications of these enthalpic changes for the mechanism of osmolyte stabilization were pointed out by Politi and Harries (37): There must be other intermolecular forces acting in addition to steric crowding. Sukenik et al categorized possible mechanisms based on the measured sign and relative magnitudes of enthalpic and entropic contributions (38). Senske et al did a similar classification of possible mechanisms for protein stabilization based on observed changes in enthalpy of unfolding and melting temperature T m (which depends also on entropy) (39).…”

“…The second difficulty is that observed effects of osmolytes and crowders on protein binding and folding often have significant enthalpic contributions (23,(37)(38)(39). Excluded volume effects are entropic, whether treated by the mean-field AO, scaled particle, or HS mixture models.…”

Effects of Hydrophobic Macromolecular Crowders on Amyloid β (16–22) Aggregation

“…We found that the relative fibril elongation rate in our simulations with 40 Å crowders has a value that is similar to the relative fibril elongation rate for insulin fibrils in the presence of 200 kDa dextran. Our relative fibril elongation rates for Ab (16)(17)(18)(19)(20)(21)(22) with 20 Å crowders are equivalent to those obtained for bovine insulin and insulin B-chain with 200 kDa dextran, and our relative fibril elongation rates for Ab (16)(17)(18)(19)(20)(21)(22) with 5 Å crowders are equivalent to those obtained for human a-synuclein and hen egg white lysozyme with 200 kDa dextran.…”

“…Experiments have been conducted to examine how attractive molecules, including osmolytes (14)(15)(16)(17)(18)(19)(20), saccharides (21), small-molecule inhibitors (22)(23)(24), and quantum dots (25), affect protein aggregation. Among these experimental studies, the most relevant to our work involved the addition of osmolytes to a system of proteins, because they employed concentrations and size scales similar to those used in our simulations.…”

“…More specifically, we applied discontinuous molecular dynamics (DMD) combined with the PRIME20 force field to a system comprised of 192 Ab (16)(17)(18)(19)(20)(21)(22) peptides and hard-sphere crowders with diameters D ¼ 5 Å , 20 Å , and 40 Å at crowder volume fractions f ¼ 0.00 and 0.10 starting from a random configuration. The major findings of that study were that 1) the addition of crowders to a system of peptides increases the rates of oligomerization and fibrillization, with higher volume fractions and smaller crowders providing the largest enhancement effects, and 2) the aggregation mechanism changes from a relatively slow-nucleated polymerization mechanism to a relatively fast-nucleated conformational conversion mechanism as the crowder volume fraction increases or the crowder diameter decreases.…”