Molecular Simulations of the Configurational Entropy of the Trp-Cage Miniprotein

Abstract

Understanding conformational entropy changes in globular protein folding is essential to both predictive models of protein structure and the development of high-affinity pharmaceuticals. The conformational entropy of the Trp-cage miniprotein is calculated using all-atom molecular dynamics simulations and the probability distributions of dihedral angles per residue. We use two force fields, Amber-99SB and Amber-94, in water and water-urea solvents in our calculations. We compute the configurational entropy using models that included correlations within individual amino acids and with nearest neighbors. We find that the entropy depends on sequence and position of the chain on the protein. Neighboring residues are shown to only have a less than 10% influence on individual residue entropies. AMBER-94 force field is shown to decrease the entropy of the alpha helical region in the unfolded state, suggesting anomalous residual helix formation in the unfolded state. Unexpectedly, the water-urea solution is shown to destabilize the alpha helical region in the folded state while stabilizing the alpha helical region in the folded state. The results of this project give new context with which to examine Flory's isolated-pair hypothesis as well as the Levinthal paradox. The results could be used to further examine the assumptions underlying the interpretation of protein NMR experiments that attempt to measure the configurational entropy. This work was done as part of an NSF REU Summer Program (Grant DMR-0850934)and MCB-0543769.