Molecular Crowders Can Induce Collapse in Hydrophilic Polymers via Soft Attractive Interactions

A comprehensive understanding of protein folding andbiomolecularself-assembly in the intracellular environment requires obtaininga microscopic view of the crowding effects. The classical view ofcrowding explains biomolecular collapse in such an environment interms of the entropic solvent excluded volume effects subjected tohard-core repulsions exerted by the inert crowders, neglecting theirsoft chemical interactions. In this study, the effects of nonspecific,soft interactions of molecular crowders in regulating the conformationalequilibrium of hydrophilic (charged) polymers are examined. Usingadvanced molecular dynamics simulations, collapse free energies ofan uncharged, a negatively charged, and a charge-neutral 32-mer genericpolymer are computed. The strength of the polymer-crowder dispersionenergy is modulated to examine its effect on polymer collapse. Theresults show that the crowders preferentially adsorb and drive thecollapse of all three polymers. The uncharged polymer collapse isopposed by the change in solute-solvent interaction energybut is overcompensated by the favorable change in the solute-solvententropy as observed in hydrophobic collapse. However, the negativelycharged polymer collapses with a favorable change in solute-solventinteraction energy due to reduction in the dehydration energy penaltyas the crowders partition to the polymer interface and shield thecharged beads. The collapse of a charge-neutral polymer is opposedby the solute-solvent interaction energy but is overcompensatedby the solute-solvent entropy change. However, for the stronglyinteracting crowders, the overall energetic penalty decreases sincethe crowders interact with polymer beads via cohesive bridging attractionsto induce polymer collapse. These bridging attractions are found tobe sensitive to the binding sites of the polymer, since they are absentin the negatively charged or uncharged polymers. These interestingdifferences in thermodynamic driving forces highlight the crucialrole of the chemical nature of the macromolecule as well as of thecrowder in determining the conformational equilibria in a crowdedmilieu. The results emphasize that the chemical interactions of thecrowders should be explicitly considered to account for the crowdingeffects. The findings have implications in understanding the crowdingeffects on the protein free energy landscapes.