Entropic formulation for the protein folding process: Hydrophobic stability correlates with folding rates

Abstract

We assume that the protein folding process follows two autonomous steps: the conformational search for the native, mainly ruled by the hydrophobic effect; and, the final adjustment stage, which eventually gives stability to the native. Our main tool of investigation is a 3D lattice model provided with a ten-letter alphabet, the stereochemical model. This model was conceived for Monte Carlo (MC) simulations when one keeps in mind the kinetic behavior of protein-like chains in solution. In order to characterize the folding characteristic time (τ) by two distinct sampling methods, first we present two sets of 10 3 MC simulations for a fast protein-like sequence. For these sets of folding times, τ and τ q were obtained with the application of the standard Metropolis algorithm (MA), and a modified algorithm (M q A). The results for τ q reveal two things: i) the hydrophobic chain-solvent interactions plus a set of inter-residues steric constraints are enough to emulate the first stage of the process: for each one of the 10 3 MC performed simulations, the native is always found without exception, ii) the ratio τ q /τ≅1/3 suggests that the effect of local thermal fluctuations, encompassed by the Tsallis weight, provides an innate efficiency to the chain escapes from energetic and steric traps. A physical insight is provided. Our second result was obtained through a set of 600 independent MC simulations performed with the M q A method applied to a set of 200 representative targets (native structures). The results show how structural patterns modulate τ q , which cover four orders of magnitude in the temporal scale. The third, and last result, was obtained from a special kind of simulation for those same 200 targets, we simulated their stability. We obtained a strong correlation (R=0.85) between the hydrophobic component of protein stability and the folding rate: the faster is the protein to find the native, larger is the hydrophobic component of its stability. This final result suggests that the hydrophobic interactions could not be a general stabilizing factor for proteins.

Variability of entropy force and its coupling with electrostatic and steric hindrance interactions

“…Hydrophobic interactions play a significant role in numerous processes occurring in aqueous solutions. These interactions are particularly important in complexation, surfactant aggregation, coagulation, molecular recognition, the development of waterproof coatings, and the formation and stabilization of proteins, biological membranes, and micelles [18][19][20][21][22]. The EIP between charged colloids in ion fluids is referred to as the effective electrostatic potential (EEP) [23][24][25][26][27][28][29][30], which arises from the interplay of electrical forces in the presence of other ions in the surrounding solution and is influenced by several factors, including surface charge, double layer, ionic J. Stat.…”