Coarse-Grained Strategy for Modeling Protein Stability in Concentrated Solutions II: Phase Behavior

¹ National Institute of Standards and Technology
² The University of Texas at Austin
³ The State University of New York at Buffalo

^* To whom correspondence should be addressed. E-mail: truskett{at}che.utexas.edu.

Submitted on October 20, 2005
Revised on November 24, 2005
Accepted on 8 December 2005

	Abstract

We use highly efficient transition-matrix Monte Carlo methods to determine equilibrium unfolding curves and fluid phase boundaries for solutions of coarse-grained globular proteins. The model we analyze [Cheung and Truskett, Biophys. J. 89, 2372 (2005)] derives the intrinsic stability of the native state and protein-protein interactions from basic information about protein sequence using heteropolymer collapse theory. We find that solutions of low hydrophobicity proteins generally exhibit a single liquid phase near their midpoint temperatures for unfolding, while solutions of proteins with high sequence hydrophobicity display the type of temperature-inverted, liquid-liquid transition associated with aggregation processes of proteins and other amphiphilic molecules. The phase transition occurring in solutions of the most hydrophobic protein we study extends below the unfolding curve, creating an immiscibility gap between a dilute `mostly native' phase and a concentrated `mostly denatured' phase. The results are qualitatively consistent with the solution behavior of hemoglobin (HbA) and its sickle variant (HbS), and they suggest that a liquid-liquid transition resulting in significant protein denaturation should generally be expected on the phase diagram of high-hydrophobicity protein solutions. The concentration fluctuations associated with this transition could be a driving force for the non-native aggregation that can occur below the midpoint temperature.

Key Words: Hydrophobic interactions, Monte Carlo simulations, Phase diagrams, Protein aggregation, Protein-protein interactions, Water

This article has been cited by other articles:

				J. K. Cheung, V. K. Shen, J. R. Errington, and T. M. Truskett Coarse-Grained Strategy for Modeling Protein Stability in Concentrated Solutions. III: Directional Protein Interactions Biophys. J., June 15, 2007; 92(12): 4316 - 4324. [Abstract] [Full Text] [PDF]

				J. K. Cheung, P. Shah, and T. M. Truskett Heteropolymer Collapse Theory for Protein Folding in the Pressure-Temperature Plane Biophys. J., October 1, 2006; 91(7): 2427 - 2435. [Abstract] [Full Text] [PDF]