Quantifying the Molecular Origins of Opposite Solvent Effects on Protein-Protein Interactions

Vincent Vagenende,Alvin X Han,Han B Pek,Bernard L W Loo,Bert L De Groot

doi:10.1371/journal.pcbi.1003072

Abstract

Although the nature of solvent-protein interactions is generally weak and non-specific, addition of cosolvents such as denaturants and osmolytes strengthens protein-protein interactions for some proteins, whereas it weakens protein-protein interactions for others. This is exemplified by the puzzling observation that addition of glycerol oppositely affects the association constants of two antibodies, D1.3 and D44.1, with lysozyme. To resolve this conundrum, we develop a methodology based on the thermodynamic principles of preferential interaction theory and the quantitative characterization of local protein solvation from molecular dynamics simulations. We find that changes of preferential solvent interactions at the protein-protein interface quantitatively account for the opposite effects of glycerol on the antibody-antigen association constants. Detailed characterization of local protein solvation in the free and associated protein states reveals how opposite solvent effects on protein-protein interactions depend on the extent of dewetting of the protein-protein contact region and on structural changes that alter cooperative solvent-protein interactions at the periphery of the protein-protein interface. These results demonstrate the direct relationship between macroscopic solvent effects on protein-protein interactions and atom-scale solvent-protein interactions, and establish a general methodology for predicting and understanding solvent effects on protein-protein interactions in diverse biological environments.

Highlights

Cosolvents such as denaturants, salts, amino acids and polyols play an important role in many protein processes as they modify the strength of intra- and intermolecular interactions of proteins in various cellular and biochemical environments [1,2,3,4,5]
Current understanding of cosolvent effects on protein interactions is largely derived from the principles of linked functions [26] and the thermodynamic theory of preferential interactions in multicomponent solutions [27,28,29,30,31,32,33,34,35,36]. These principles dictate that the addition of cosolvent will shift the association constant KA of two proteins towards the protein state with the highest preferential interaction coefficient CXP [6,37,38]: d d ln ln Solvents play a fundamental role in living systems where they mediate the interactions between proteins and other biomolecules
Our results demonstrate the direct relationship between solvent effects on proteinprotein interactions and local solvent-protein interactions, and establish a general methodology for predicting and understanding cosolvent effects on protein-protein interactions in diverse biological environments

Summary

Introduction

Cosolvents such as denaturants, salts, amino acids and polyols play an important role in many protein processes as they modify the strength of intra- and intermolecular interactions of proteins in various cellular and biochemical environments [1,2,3,4,5]. Excluded cosolvents generally stabilize proteins, whereas cosolvents that preferentially interact with the protein surface often destabilize and denature proteins [6,17]. It is often implied that preferentially excluded cosolvents increase protein-protein interactions, whereas cosolvents that preferentially interact with the protein surface weaken protein-protein interactions. This dichotomy is, irreconcilable with many studies in literature that report specific – and even opposite – effects of cosolvents on protein-protein interactions [9,18,19,20,21,22,23]

Methods

Results

Discussion

Conclusion