The Effect of Molecular Crowding on the Stability of Peptides

Abstract

We use Replica Exchange Statistical Temperature Molecular Dynamics (RESTMD) to investigate the effects of molecular crowding on the structure and thermodynamics of several test peptides. The test peptides are small, biologically relevant peptide that have a dominant secondary structure (either all helical or a β-barrel) and are represented via a coarse-grained computational model where the side chain - side chain interactions are based on a statistical analysis of the Protein Data Bank. The crowding agents are also peptides and are represented by the same coarse-grained model. The RESTMD algorithm naturally calculates the density of states of the system enabling us to analyze the entropic and enthalpic effects of crowding separately. The entropic effects of crowding lead to a stabilization of the test peptide relative to dilute solution. Of particular interest are the enthalpic effects, which can be either stabilizing or destabilizing. The destabilization can be large enough to overcome the entropic stabilization, resulting is a peptide that is destabilized in a crowded environment. We investigate the effect of different crowder hydrophobicities on the enthalpic contribution to the (de)stabilization of the test peptide. We show that there is a crossover temperature below which crowding agents destabilize a peptide and above which the same crowding agents stabilize it and relate this crossover temperature to the hydrophobic nature of the crowders. In addition, we will discuss the effect that crowding has on secondary structure content of the test peptides.