A generic model for pH-sensitive collapse of hydrophobic polymers

Abstract

The hydrophobic effect is an important contributor to the stability of proteins and may be influenced by many factors including the pH of the solution. To simplify the study of pH effects on proteins, we parameterize biologically motivated titratable monomers which we insert into the sequence of a hydrophobic polymer and study via constant pH molecular dynamics (MD) simulations. We calculate the potential of mean force of the polymer as a function of its radius of gyration at different pH values and observe that the collapsed state of the polymer is destabilized when the titratable monomer is more charged (high pH for an acid and low pH for a base). Further, the extent of the destabilization is influenced by the position of the titratable monomer along the polymer sequence. The pK_a value of the titratable monomer is also observed to be sensitive to polymer conformation, in agreement with protein studies. We further study a zwitterionic polymer with an acidic and a basic monomer in the same sequence which presents a pH-dependent hairpin formation. Our model provides a simplified yet powerful framework to study pH effects on the hydrophobic effect, providing insights into mechanisms governing the behavior of intrinsically disordered proteins (IDPs) and pH-sensitive drug delivery, among other applications.