Rational design of solution additives for the prevention of protein aggregation

Rational design of solution additives for the prevention of protein aggregation
Engineering Village 2
2006 Elsevier Inc.
Accession number: 8256671

Title: Rational design of solution additives for the prevention of protein aggregation

Authors: Baynes, B.M.1 ; Trout, B.L.1

Author affiliation: 1 Dept. of Chem. Eng., MIT, Cambridge, MA, USA

Serial title: Biophysical Journal

Abbreviated serial title: Biophys. J. (USA)

Volume: 87

Issue: 3

Publication date: Sept. 2004

Pages: 1631-9

Language: English

ISSN: 0006-3495


Document type: Journal article (JA)

Publisher: Biophys. Soc

Country of publication: USA

Material Identity Number: B154-2004-011

Abstract: We have developed a statistical-mechanical model of the effect of solution additives on protein association reactions. This model incorporates solvent radial distribution functions obtained from all-atom molecular dynamics simulations of particular proteins into simple models of protein interactions. In this way, the effects of additives can be computed along the entire association/dissociation reaction coordinate. We used the model to test our hypothesis that a class of large solution additives, which we term "neutral crowders", can slow protein association and dissociation by being preferentially excluded from protein-protein encounter complexes, in a manner analogous to osmotic stress. The magnitude of this proposed "gap effect" was probed for two simple model systems: the association of two spheres and the association of two planes. Our results suggest that for a protein of 20 ? radius, an 8 ? additive can increase the free energy barrier for association and dissociation by as much as 3-6 kcal/mol. Because the proposed gap effect is present only for reactions involving multiple molecules, it can be exploited to develop novel additives that affect protein association reactions although having little or no effect on unimolecular reactions such as protein folding. This idea has many potential applications in areas such as the stabilization of proteins against aggregation during folding and in pharmaceutical formulations

Number of references: 36

Inspec controlled terms: association - biochemistry - dissociation - free energy - molecular biophysics - molecular dynamics method - physiological models - proteins - solutions

Uncontrolled terms: solution additives - protein aggregation - statistical-mechanical model - protein association reactions - solvent radial distribution functions - all-atom molecular dynamics simulations - protein interactions - dissociation - protein-protein encounter complexes - osmotic stress - free energy barrier - gap effect - protein folding - 20 angstrom - 8 angstrom

Inspec classification codes: A8715P Model reactions in molecular biophysics - A8715K Biomolecular interactions, charge transfer complexes - A8715H Biomolecular dynamics, molecular probes, molecular pattern recognition - A8230N Association, addition, and insertion - A8230L Decomposition reactions (pyrolysis, dissociation, and group ejection) - A3620 Macromolecules and polymer molecules - A0260 Numerical approximation and analysis - A8710 General, theoretical, and mathematical biophysics

Numerical data indexing: size 4.0E-09 m;size 8.0E-10 m

Treatment: Theoretical or Mathematical (THR)

Discipline: Physics (A)

DOI: 10.1529/biophysj.104.042473

Database: Inspec

Copyright 2005, IEE
Subscription required: http://www.engineeringvillage2.org
Comments: 0