Coarse-grained strategy for modeling protein stability in concentrated solutions

¹ The University of Texas at Austin

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

Submitted on February 28, 2005
Revised on April 24, 2005
Accepted on 15 July 2005

	Abstract

We present a coarse-grained approach for modeling the thermodynamic stability of single-domain globular proteins in concentrated aqueous solutions. Our treatment derives effective protein-protein interactions from basic structural and energetic characteristics of the native and denatured states. These characteristics, along with the intrinsic (i.e., infinite dilution) thermodynamics of folding, are calculated from elementary sequence information using a heteropolymer collapse theory. We integrate this information into Reactive Canonical Monte Carlo simulations to investigate the connections between protein sequence hydrophobicity, protein-protein interactions, protein concentration, and the thermodynamic stability of the native state. The model predicts that sequence hydrophobicity can affect how protein concentration impacts native-state stability in solution. In particular, low hydrophobicity proteins are primarily stabilized by increases in protein concentration, while high hydrophobicity proteins exhibit richer non-monotonic behavior. These trends appear qualitatively consistent with the available experimental data. Although factors such as pH, salt concentration, and protein charge are also important for protein stability, our analysis suggests that some of the nontrivial experimental trends may be driven by a competition between destabilizing hydrophobic protein-protein attractions and entropic crowding effects.

Key Words: Coarse-grained, Concentration effects, Crowding, Heteropolymer collapse, Protein stability, Protein-protein interactions

This article has been cited by other articles:

				G. Wieczorek and P. Zielenkiewicz Influence of Macromolecular Crowding on Protein-Protein Association Rates--a Brownian Dynamics Study Biophys. J., December 1, 2008; 95(11): 5030 - 5036. [Abstract] [Full Text] [PDF]

				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]

				V. K. Shen, J. K. Cheung, J. R. Errington, and T. M. Truskett Coarse-Grained Strategy for Modeling Protein Stability in Concentrated Solutions. II: Phase Behavior Biophys. J., March 15, 2006; 90(6): 1949 - 1960. [Abstract] [Full Text] [PDF]