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Abstract
A didactic model is presented to illustrate how the effect of macromolecular crowding on protein folding and association is modeled using current analytical theory and discrete molecular dynamics. While analytical treatments of crowding may consider the effect as a potential of average force acting to compress a polypeptide chain into a compact state, the use of simulations enables the presence of crowding reagents to be treated explicitly. Using an analytically solvable toy model for protein folding, an approximate statistical thermodynamic method is directly compared to simulation in order to gauge the effectiveness of current analytical crowding descriptions. Both methodologies are in quantitative agreement under most conditions, indication that both current theory and simulation methods are capable of recapitulating aspects of protein folding even by utilizing a simplistic protein model.
Highlights
Current information about the relative stability of native and non-native conformations of proteins is derived largely from experiments carried out on dilute solutions of protein subjected to variations in temperature and pH, or addition of chaotropic agents or osmolytes [1,2,3]
The discretized one-dimensional potential of average force specified in Table 1 was designed to qualitatively imitate features of a real protein, ribonuclease A, as shown in Figs. 1 and 2, we emphasize that this model is not meant to physically represent the actual process of protein folding
Our model provides didactic value such that the most fundamental elements of protein folding, namely the interplay between short-ranged and long-ranged interactions, are retained at a simplistic level to enable exploration of the features of macromolecular crowding using statistical thermodynamic theory
Summary
Current information about the relative stability of native and non-native conformations of proteins is derived largely from experiments carried out on dilute solutions of protein subjected to variations in temperature and pH, or addition of chaotropic agents or osmolytes [1,2,3]. Thermodynamic considerations dictate that the stability of a particular protein in dilute solution is directly linked to the difference between the respective free energies of nonspecific interaction of the native and non-native conformations of the selected protein and the macromolecular constituents of the surrounding medium [10,11] Such interactions may be of any kind, in the present work we focus upon intermolecular excluded volume interactions, or steric repulsions. Such interactions are ubiquitous in highly volume-occupied physiological fluid media, and result in significant size- and shape-dependent repulsive contributions to the chemical potential of each macromolecular species that tend to stabilize more compact conformations relative to less-compact conformations [12,13]. In this context we shall refer to macromolecules in the environment interacting with target protein via steric exclusion as ‘‘crowders’’
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